Acquired resistance to molecularly targeted therapies for cancer
0 Abstract
Acquired resistance to molecularly targeted therapies remains a formidable challenge in the treatment of cancer, despite significant advancements over the last several decades. We critically evaluate the evolving landscape of resistance mechanisms to targeted cancer therapies, with a focus on the genetic, molecular, and environmental contributors across a variety of malignancies. Intrinsic mechanisms such as mutations, drug and drug target modifications, and, notably, the activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt pathways are mechanisms different malignancies use to combat therapeutic effectiveness. Furthermore, extrinsic alterations to the tumor microenvironment contribute to therapeutic resistance. We highlight similarities and differences in mechanisms across a wide spectrum of cancers including hematologic malignancies, non-small cell lung cancer, gastrointestinal, breast, and prostate cancers, pancreatic, ovarian, endometrial, and intracranial gliomas. Emerging strategies to overcome resistance, including multi-targeted approaches, combination therapies, and exploitation of synthetic lethality, are all critically discussed. We advocate for a nuanced understanding of resistance mechanisms as a cornerstone for developing future therapeutic strategies, emphasizing the necessity for integrated approaches that encompass genomic insights and precision medicine to outpace the dynamic and complex nature of cancer evolution and therapy resistance.
Keywords
INTRODUCTION
Global cancer burden and epidemiological trends
Cancer ranks as a leading cause of disease-related mortality across the globe. Per projections, this burden is estimated to increase by 47% in 20 years[1]. This alarming trend is hypothesized to be driven by an aging population, an increasing amount of exposure to environmental carcinogens, evolving dietary patterns, physical inactivity, and rising obesity rates in both high-income and low- to middle-income countries (LMICs)[1,2]. Importantly, the distribution of cancer types and risk factors varies considerably across geographic regions. This is reflected via the differences in healthcare infrastructure, screening programs, and prevalence of infectious agents associated with malignancies [i.e., hepatitis B virus (HBV) and human papillomavirus (HPV)][1].
Disparities in access to targeted therapies and precision oncology also contribute to global inequalities in cancer outcomes. While molecularly targeted therapies (MTTs) have revolutionized treatment paradigms in well-resourced settings, patients in resource-limited regions often lack access to genetic testing required to identify actionable mutations. This results in delayed diagnosis, inappropriate treatment selection, and poorer survival outcomes. Therefore, discussions of acquired resistance in targeted therapies must account for global treatment gaps, acknowledging that resistance dynamics in high-resource settings - where molecular profiling is routine - may differ significantly from those in settings where empirical therapy is the norm[3,4].
As MTTs become more affordable and accessible globally, understanding the interplay between tumor biology, treatment access, and socio-environmental factors will be crucial for designing resistance-prevention strategies that are relevant across diverse populations[1,3,4]. This globalized perspective not only enhances scientific relevance but also aligns with the broader goals of reducing global cancer health disparities through the equitable application of precision medicine. All that being said, it is imperative for researchers and scientists alike to formulate and implement effective treatment approaches for patients with cancer[1,2].
Precision oncology and MTTs
Since their initial clinical endorsement in the late 1990s, MTTs have shown pronounced anticancer capabilities for both specific cancers and across cancer types. These therapies, which include small molecule inhibitors and therapeutic monoclonal antibodies that block signal transduction, have become integral to precision oncology. In 2001, the US Food and Drug Administration (FDA) approved imatinib, the first small-molecule targeted drug to be authorized for clinical use against chronic myeloid leukemia (CML)[3,4]. Since then, there has been a dramatic increase in the production of drugs. There are currently 89 small-molecule targeted anticancer drugs that have been approved by the US FDA and National Medical Products Administration (NMPA) of China[5]. An overview of representative MTTs including their mechanisms of action, associated resistance pathways, and clinical indications is provided in Table 1. While this has dramatically changed the way cancer is treated, the challenge of acquired resistance has sparked an ongoing struggle to understand how to effectively manage tumor growth.
Overview of MTTs and resistance mechanisms
| Drug | Class | Target(s) | Mechanism of action | Resistance mechanisms | Tumor type(s) |
| Vincristine | Vinca alkaloid | Tubulin | Inhibits microtubule formation → mitotic arrest | P-gp overexpression, tubulin mutations | Leukemia, lymphoma |
| Trastuzumab | Monoclonal antibody | HER2 | Blocks HER2 dimerization and signaling, induces ADCC | HER2 mutations, pathway bypass, TME effects | Breast cancer |
| Ponatinib | TKI | BCR-ABL1 (incl. T315I) | ATP-binding site inhibition | Compound mutations, efflux, microenvironment interactions | CML, Ph+ ALL |
| Imatinib | TKI | BCR-ABL1 | Competitive ATP-binding site inhibition | BCR-ABL mutations (esp. T315I) | CML, Ph+ ALL |
| Bosutinib | TKI | BCR-ABL1 | ATP-binding site inhibition | BCR-ABL mutations, off-target toxicity | CML |
| Asciminib | STAMP inhibitor | BCR-ABL1 (Myristoyl pocket) | Allosteric inhibition | Emergent compound mutations | CML |
| Blinatumomab | Bispecific antibody | CD19 | T-cell engagement and cytotoxicity | CD19 downregulation, lineage switch | B-ALL (including Ph+ ALL) |
| TMZ | Alkylating agent | DNA | DNA methylation at O6-guanine | MGMT overexpression | Glioblastoma |
| Bevacizumab | Monoclonal antibody | VEGF | Neutralizes VEGF | Alternate angiogenesis pathways | Glioblastoma, colorectal cancer, NSCLC |
| Erlotinib | TKI | EGFR | ATP-competitive EGFR inhibition | EGFR T790M mutation, MET amplification | NSCLC |
| Osimertinib | TKI | EGFR (T790M) | Irreversible covalent inhibition | EGFR C797S mutation, bypass pathways | NSCLC |
| Gefitinib | TKI | EGFR | ATP-competitive EGFR inhibition | EGFR T790M mutation, MET amplification | NSCLC |
| Crizotinib | TKI | ALK, MET | ATP-competitive inhibition | ALK resistance mutations (L1196M) | NSCLC |
| Ceritinib | TKI | ALK | ATP-competitive inhibition | ALK mutations, bypass signaling | NSCLC |
| Lorlatinib | TKI | ALK | ATP-competitive inhibition | Complex ALK mutations, off-target effects | NSCLC |
| Vemurafenib | TKI | BRAF V600E | Selective mutant BRAF inhibition | MEK reactivation, alternate splicing | Melanoma |
| Dabrafenib | TKI | BRAF V600E | Selective mutant BRAF inhibition | MEK reactivation, alternate splicing | Melanoma |
| Trametinib | MEK inhibitor | MEK1/2 | Inhibits MEK kinase activity | Secondary MEK mutations, pathway reactivation | Melanoma |
| Sunitinib | TKI | VEGFR, PDGFR | Multikinase inhibition | Hypoxia-induced resistance, alternative angiogenesis | Renal cell carcinoma, GIST |
| Sorafenib | TKI | RAF, VEGFR, PDGFR | Multikinase inhibition | Adaptive hypoxia response | Hepatocellular carcinoma, renal cell carcinoma |
| Olaparib | PARP inhibitor | PARP1/2 | Inhibits DNA repair | HR proficiency, replication fork protection | OvCa, breast cancer |
| Niraparib | PARP inhibitor | PARP1/2 | Inhibits DNA repair | HR proficiency, replication fork protection | OvCa |
| Rucaparib | PARP inhibitor | PARP1/2 | Inhibits DNA repair | HR proficiency, replication fork protection | OvCa |
| Pembrolizumab | Checkpoint inhibitor | PD-1 | Blocks PD-1/PD-L1 interaction | Immunoediting, loss of MHC expression | Melanoma, NSCLC |
| Nivolumab | Checkpoint inhibitor | PD-1 | Blocks PD-1/PD-L1 interaction | Immunoediting, loss of MHC expression | Melanoma, NSCLC |
FOUNDATIONS OF THERAPEUTIC RESISTANCE
Defining therapeutic resistance
Resistance to MTTs can be separated into two categories: Intrinsic (primary), where resistance mechanisms pre-exist prior to therapy initiation, or acquired, where therapy itself exerts selective pressure that promotes clonal evolution and survival of resistant subpopulations[6]. Acquired resistance often reflects a dynamic process involving genomic instability, epigenetic reprogramming, and interaction with the tumor microenvironment (TME), all of which promote a more treatment-refractory tumor phenotype[7]. Due to the evolutionary aspect of this concept and the difficulty encountered when attempting to address these changes, acquired resistance will remain the main focus of this manuscript.
The causes of acquired resistance are varied and can involve many different aspects including drug-target modifications, alternative signaling pathway activation, and/or shifts in the TME usually initiated by genetic adaptations[8]. Understanding the mechanisms surrounding different treatment failures is vital for improving patient outcomes, as this will help us develop new treatment strategies and therapeutic targets.
Key pathways underpinning resistance dynamics
Before diving into the various mechanisms of resistance to MTTs, it is important to gain an understanding of signaling pathways that promote tumorigenesis. The landscape of cancer resistance mechanisms is significantly influenced by the reconfiguration of key cellular signaling pathways, notably the mitogen-activated protein kinase (MAPK) and the phosphoinositide 3-kinase–protein kinase B/Akt (PI3K-PKB/Akt) pathways[9,10]. These pathways play pivotal roles in the survival, proliferation, and therapy resistance observed across various cancer types. Thus, understanding how these pathways contribute to resistance is vital for the development of effective counterstrategies.
MAPK
The MAPK pathway is integral to the regulation of cell growth and survival, as shown in Figure 1. Activation of this pathway begins at the cell membrane with the binding of growth factors to their respective receptor tyrosine kinases (RTKs), which, in turn, activate their associated RAS GTPases to relay signals downstream[11]. RAF family kinases (ARAF, BRAF, CRAF) are the direct effectors of RAS, which phosphorylates and activates MEK, to then phosphorylate ERK, which translocates to the nucleus to regulate gene expression by activating transcription factors[11]. The linear progression from growth factor stimulation to transcriptional regulation underscores the MAPK pathway’s pivotal role in mediating cellular responses to external cues. The MAPK pathway also has crosstalk with other signaling pathways, including PI3K/Akt, where mTORC2 appears to convey a portion of the oncogenic Ras signal in melanoma and likely in other contexts[11].
Figure 1. Schematic representation of parallels between PI3K/Akt and MAPK signal pathways. Both pathways become activated when growth factors bind to their respective RTKs, causing RAS GTPases to relay signals downstream. Activation of these pathways promotes increased cell proliferation and survival. Some of the intricacies in signaling by mTORC1 and mTORC2 are shown leading to some distinct effects on metabolism and cell fate. PI3K: Phosphoinositide 3-kinase; Akt: protein kinase B; MAPK: mitogen activated protein kinase; RTK: receptor tyrosine kinase; RAS: oncogene; PTEN: phosphatase and tensin homolog; PIP2: phosphatidylinositol 4,5-bisphosphate; PIP3: phosphatidylinositol 3,4,5-triphosphate; PDK1: 3-phosphoinositidedependent protein kinase 1; mTORC1: mTOR complex 1; mTORC2: mTOR complex 2; RAF: rapidly accelerated fibrosarcoma; MEK: mitogen-activated extracellular signal-regulated kinase; ERK: extracellular signal-related kinase. Created in BioRender. Purcell, C. (2025) https://BioRender.com/3us5vg.
Mutations in any components of this pathway, particularly in RAS or RAF, can lead to its constitutive activation, driving oncogenesis by promoting uncontrolled cell proliferation and survival. For example, in melanoma, the BRAF V600E mutation results in constitutive activation of the MAPK pathway, promoting uncontrolled cell growth. Though BRAF inhibitors were initially impactful for melanoma, resistance, particularly to vemurafenib, eventually emerged, facilitated by secondary mutations reactivating the MAPK pathway. Much like the initial base switch mutation that causes permanent activation of BRAF, base switch mutations in MEK1 and MEK2 can also cause them to become aberrantly activated and continue to affect downstream pathways[12]. Other mechanisms known to cause resistance include overexpression and resultant amplification of the RAF kinases (BRAF, CRAF) along with downstream activating mutations in N-RAS, MEK1, or Akt1[13-16].
PI3K/Akt
Parallel to the MAPK pathway, the PI3K/Akt pathway plays a crucial role in cancer cell metabolism, growth, and survival, as seen in Figure 1. This pathway’s activation also begins with the binding of growth factors to the extracellular regions of their respective RTKs and GPCRs[17,18]. Upon activation, RTKs recruit and activate the PI3K. Once turned on, these PI3Ks catalyze downstream reactions, which eventually recruit Akt to the plasma membrane for further mediators like 3-phosphoinositidedependent protein kinase 1 (PDK1) and mTOR complex 2 (mTORC2) to act on it, activate it, and facilitate a myriad of downstream targets to increase cell proliferation and survival[17].
In discussing tumorigenesis, this pathway is constantly activated following either mutations in PIK3CA or the loss of the tumor suppressor PTEN, which acts as a key regulator of Akt activation[19]. When discussing melanoma and BRAF resistance, the PI3K pathway is often implicated as a bypass mechanism conferring survival following targeted therapy[20,21]. The interaction between the MAPK and PI3K/Akt pathways exemplifies the complexity of intracellular signaling networks and their role in cancer resistance. Crosstalk between these pathways allows cancer cells to maintain proliferative and survival signaling even when one pathway is pharmacologically inhibited. The scenario can be even more complicated by NRAS mutations, present in a notable subset of melanomas[22]. Alterations in NRAS lead to activation of the RAS-RAF-MAPK and PI3K-Akt pathways at similar levels seen with BRAF mutations[22,23]. Furthermore, NRAS mutations rarely occur with changes in the PI3K-Akt pathways, suggesting a dominant role for NRAS mutations in these signaling processes. As a result, there is a disruption in cell cycle regulation that promotes survival mechanisms and cellular proliferation[22]. As BRAF inhibitors are seemingly ineffective in these tumors, the development of downstream MEK inhibitors served the purpose of slowing growth in these tumors[24,25]. Unfortunately, however, MEK frequently mutates following MEKi treatment, resulting in either overactivation of MEK or the inability of the inhibitor to bind MEK[26,27]. This crosstalk is particularly evident as the mutations lead to concurrent activation of both pathways, presenting a significant challenge to single-targeted therapies.
EGF/EGFR
Beyond the PI3K/Akt and MAPK pathways, the EGF/EGFR signaling axis also plays a pivotal role in resistance development[28]. EGFR overexpression, activating mutations, and autocrine signaling loops contribute to both intrinsic and acquired resistance. Additionally, the tumor suppressor PTEN - an upstream regulator of the PI3K pathway - is frequently lost or mutated in resistant cancers, further amplifying downstream survival signaling[29]. The insulin-like growth factors (IGFs) and their receptors also play a role, driving pro-survival signals and metabolic reprogramming that enhances cancer cell fitness under therapeutic pressure[30,31].
THE TME AND THERAPY RESISTANCE
Definition and core components of the TME
The interaction between cancer cells and their surrounding TME plays another important role in developing resistance to targeted therapies[32]. The TME is a supportive meshwork of biological components that aid in the growth and development of a tumor[33-35]. More specifically, these components are immune cells, stromal cells, extracellular matrix (ECM), extracellular vesicles (EVs), cytokines, and growth factors[33-35]. Collectively, these elements contribute significantly to therapeutic resistance through direct and indirect interactions with cancer cells.
Myeloid cells and resistance
Tumor-associated macrophages (TAMs) originate from bone marrow and play an important role in the TME and subsequent therapeutic resistance[36-38]. Studies have shown that TAMs can directly induce epithelial-to-mesenchymal transition (EMT) of tumor cells and are heavily involved in ECM remodeling of the TME[36-38]. Activation of EMT induces stem cell properties in cancer cells[36-38]. Cancer cells with stem cell properties are known to be resistant to various treatments, including chemotherapy, targeted therapy, radiation, and immunotherapies. EMT inducers, such as transforming growth factor-β (TGF-β)[39] and tumor necrosis factor-α (TNF-α), are secreted by TAMs along with proteases like cathepsins and matrix metalloproteinases (MMPs) to help to facilitate ECM degradation. Thus, there is subsequent enhanced tumor cell motility and therapeutic resistance. The role of TAMs also extends to promoting angiogenesis within the tumor tissue, which supports tumor growth and subsequent expansion.
Myeloid-derived suppressor cells (MDSCs) can also impact tumor therapeutic resistance by promoting an immunosuppressive environment within the TME[40]. For example, it has been shown that MDSCs secrete interleukin 10 (IL-10), which serves to inhibit macrophage activation and consequently reduces the secretion of immunogenic cytokines, thereby dampening intratumoral immunity[41]. This suppression of immune activity contributes to an environment where tumor cells can evade immune surveillance and resist therapeutic interventions.
Stromal cells and resistance
Beyond myeloid cells, cancer-associated fibroblasts (CAFs) within the TME can also play a pivotal role in modulating cancer resistance[42]. Like TAMs and MDSCs, CAFs secrete proteins, exosomes, and factors involved in ECM remodeling[42]. Furthermore, these factors can influence tumor cells in a paracrine manner and activate signaling pathways such as Wnt/β-catenin, PI3K/Akt, and MAPK[43-45]. CAFs also secrete growth factors such as TGF-β, fibroblast growth factor (FGF), epidermal growth factor (EGF), and hepatocyte growth factor (HGF) to induce EMT-like CAMs and exacerbate the aggressiveness and resistance of tumor cells[46].
Role of EVs in therapy resistance
EVs are increasingly recognized as critical mediators of drug resistance in cancer[47-49]. These vesicles facilitate intercellular communication by transferring oncogenic proteins, drug-efflux pumps, and non-coding RNAs between cancer cells, thereby spreading resistance traits across the tumor population[47-49]. For example, EVs derived from resistant tumors have been shown to deliver P-glycoprotein to neighboring sensitive cells, promoting multidrug resistance[47-49]. Additionally, EVs play an important role in remodeling the TME, modulating immune evasion, and promoting angiogenesis, all of which contribute to the development of resistance[50].
ACQUIRED RESISTANCE MECHANISMS ACROSS CANCER TYPES
Following the preview of the underlying pathways that contribute to therapy resistance and the multifaceted role of the TME in fostering these resistances, we can now pivot our attention toward a comprehensive examination of acquired resistance mechanisms as they unfold across a spectrum of cancer types. Each cancer type presents unique challenges and elucidates the adaptive nature of cancer cells in the face of targeted therapies. This section aims to highlight the nuanced intricacies of resistance mechanisms, providing a foundation for the development of more effective, multifaceted treatment strategies that anticipate and counteract these adaptive responses.
Genetic and molecular basis of resistance in hematologic malignancies
The battle against hematologic malignancies, particularly CML and acute lymphocytic leukemia (ALL), has been at the forefront of personalized medicine, driven by the advent of MTTs. However, the emergence of acquired resistance represents a formidable challenge, undermining the efficacy of these treatments and complicating patient management strategies.
CML and therapeutic resistance
In the context of CML, the main driver mutation is a t(9;22)(q34;q11) balanced reciprocal translocation event, which results in the formation of the Philadelphia chromosome characterized by a BCR:ABL1 fusion gene[51]. This gene encodes a constitutively active tyrosine kinase, resulting in an unchecked myeloproliferative state diagnostic of CML[51]. The Philadelphia chromosome, resulting from the t(9;22) translocation, occurs in approximately 25% of adult ALL cases and 2%-5% of pediatric ALL cases, significantly influencing treatment decisions and prognosis[52]. From this finding, the focus shifted to the manufacturing of tyrosine kinase inhibitors (TKIs) like imatinib, bosutinib, dasatinib, and nilotinib and helped to revolutionize CML treatment. Although not considered curative, they are effective for the long-term prevention of disease progression in a majority of individuals with life expectancy in patients with CML nearing that of the general population[53-56]. In chronic-phase CML, TKI therapy has achieved remarkable success, with 5-year overall survival rates exceeding 90%. In contrast, the prognosis for Ph+ ALL remains more guarded, with 5-year survival rates in relapsed or refractory cases below 50%, even with newer therapies[53-56]. Despite this progress, unfortunately, approximately 20% of patients develop resistance to first-line TKIs. This most commonly occurs through the development of point mutations in the catalytic domain of the BCR:ABL1 protein, rendering first-line agents ineffective[53-56]. The most famous and prominent resistance mutation is the T315I mutation, as it notoriously confers resistance to all first-line TKI treatments[57-59]. This results in the use of alternative, more toxic agents to slow the progression of disease.
Beyond the BCR:ABL1-specific forms of resistance, independent forms may be acquired through TKI-resistant leukemic stem cells, which can act as a reservoir for the propagation of new tumor cells once treatment stops[59]. Oftentimes, in BCR:ABL1-independent TKI-resistant CML, the RAF/MEK/ERK pathway will be activated through the increased expression of PKCη, whose subsequent phosphorylation of CRAF leads to increased proliferation and cell survival[60]. Resistance may also occur through the improper activation of the mTOR pathway, which induces aberrant autophagy that protects cells from TKI-induced apoptosis[61]. Both pathways may be activated irrespective of BCR:ABL1 signaling[60,61]. The aforementioned mechanism of resistance underlines the multifaceted nature of this disease, highlighting the necessity for comprehensive treatment approaches[57-59]. A recent breakthrough in CML management is asciminib, a first-in-class STAMP inhibitor targeting the ABL myristoyl pocket[60]. Unlike ATP-competitive TKIs, asciminib offers a novel mechanism that bypasses several common resistance mutations, including T315I. Clinical trials such as ASCEMBL have demonstrated superior efficacy and safety compared to bosutinib in resistant chronic-phase CML[62,63].
ALL and therapeutic resistance
In a similar fashion to CML, ALL arises through the uncontrolled proliferation of lymphocyte precursor cells in the bone marrow and peripheral blood. Seventy-five percent of these cancers develop from precursors of the B cell lineage and the remaining twenty-five percent are derived from the T cell lineage[64]. Like many other hematologic malignancies, the genetic architecture of this disease is highly heterogeneous, with diverse mutations arising and frequent chromosomal translocation events even resulting in the occasional development of the Philadelphia chromosome much like CML[65,66]. In the case of Philadelphia chromosome-positive ALL, treatment with a TKI like imatinib is the current standard of care like CML, and thus, similar resistance mechanisms are likely to arise[67,68]. For Philadelphia chromosome-negative ALL, the highly efficacious treatment combination of anthracycline-like drugs, vincristine, and glucocorticoids (GC) results in complete remission for 80% of patients[68]. Vincristine, a vinca alkaloid chemotherapy agent, binds to tubulin, which inhibits microtubule formation during mitosis and eventually leads to cell cycle arrest in metaphase[69]. This mechanism makes it particularly effective against rapidly dividing cancer cells, such as those found in leukemias and lymphomas. Additionally, analogous to CML, the good prognosis of primary ALL is often overshadowed by dismal recurrence rates. In Ph+ ALL, ponatinib - a third-generation TKI - is particularly effective against the T315I mutation and is now considered a preferred frontline option in combination with reduced-intensity chemotherapy[70-74]. By binding the ATP-binding site of the BCR-ABL1 fusion protein, ponatinib blocks oncogenic signaling that drives proliferation and survival in Philadelphia chromosome-positive (Ph+) leukemias[70-74]. Its broad kinase inhibition profile also targets several off-target kinases, contributing to its efficacy, but also to its toxicity profile[70-74]. Furthermore, chemotherapy-free regimens combining ponatinib with blinatumomab, a CD19-targeting bispecific antibody, show promising efficacy in both frontline and relapsed settings[75]. Despite ponatinib’s potency, resistance can still emerge through compound mutations in BCR-ABL1, altered drug efflux, and leukemic microenvironment interactions[74].
Anthracycline resistance is most commonly acquired through the increased expression of efflux ATP-binding cassettes (ABC)-transporters, reducing intracellular drug concentration[76]. For vincristine, there is evidence that resistance is acquired through mutations that can stabilize microtubules, offsetting the primary mechanism of therapeutic action[69]. Furthermore, resistance to GCs and subsequent relapse has been observed when mutations develop in the NR3C1 and BTG1 genes, which encode for the GC receptor and promote increased GC receptor expression, respectively[77,78]. BTG1 has been shown to stabilize glucocorticoid receptors (GR) by interfering with proteasome-mediated receptor degradation, thereby increasing receptor abundance and potentiating glucocorticoid signaling in lymphoid malignancies[77]. Like many cancers, increased RAF/MEK/ERK signaling has also been associated with relapse and GC resistance[78].
Pathway reconfiguration and drug resistance in solid tumors
Moving from the genetic and molecular landscape characterizing resistance in hematologic malignancies, the realm of solid tumors unfolds a distinct yet intricate narrative. Non-small cell lung carcinoma (NSCLC), gastrointestinal cancers, prostate cancer (PCa), breast cancer, ovarian cancer (OvCa), glioblastoma, and pancreatic cancer epitomize the sophisticated mechanisms through which solid tumors counteract targeted therapies.
NSCLC and tyrosine kinase
NSCLC serves as a primary case study in the adaptation against targeted treatments, especially against tumors harboring specific genetic markers like EGFR mutations and ALK rearrangements. NSCLC comprises up to 85% of lung cancer in the US, with development being due to driver mutations of different tyrosine kinases like KRAS, EGFR, ALK, ROS1, MET, RET, NTRK, human epidermal growth factor receptor 2 (HER2), and BRAF[79,80]. Much like what was discussed in CML, the discovery of these constitutively active receptors led to the development of molecular targeted therapies, with those against EGFR and ALK being the most efficacious[81].
Despite the high initial response rates, NSCLC widely develops resistance through several proposed mechanisms, including on-target mutations, off-target mutations. On-target drug resistance occurs via a secondary mutation in the drug target. For instance, with first- and second-generation EGFR inhibitors, many EGFR-mutant NSCLC patients developed the T790M gatekeeper mutation, which hinders the drug from interacting with the kinase[82]. Analogously, the ALK mutation L1196M has been characterized as a gatekeeper mutation, preventing ALK inhibitors like crizotinib access to the kinase’s ATP binding site[83]. Though less common, another potential mechanism of on-target resistance is the amplification of the target kinase itself, which has been described for both EGFR and ALK[84,85]. The amplification of target genes, such as EGFR and ALK, further demonstrates how cancer cells can override the blockade established by targeted drugs, maintaining proliferative signaling despite treatment[86,87]. While direct modulation of treatment effect is paramount in TKI resistance in NSCLC, off-target mechanisms can essentially work in parallel to further diminish treatment efficacy following exposure to the drug. An example of such a mechanism is exemplified by the amplification of c-MET (an alternative tyrosine kinase), which can operate in parallel to EGFR and activate the same PI3K/Akt pathway, thereby negating the therapeutic benefit of EGFR inhibition[86]. This highlights the intricate web of signaling pathways within cancer cells and their inherent capacity to find alternate survival routes under therapeutic pressure.
Gastrointestinal carcinoma and 5-fluorouracil resistance
5-fluorouracil (5-FU) has been recognized as a cornerstone in therapeutic efficacy in the domain of gastrointestinal carcinoma (GIC)[87]. Unfortunately, therapeutic efficiency has diminished as resistance to this agent started to emerge. Mechanisms such as enhanced DNA repair mechanisms, shifts in drug metabolism, and the activation of survival pathways collectively forge a robust front against 5-FU.
Enhanced DNA repair, specifically through the base excision repair (BER) and mismatch repair (MMR) pathways, has been shown to play significant roles in promoting resistance to 5-FU[88,89]. The APC gene, identified as a BER-related protein, is notable in this context as tumors lacking functional APC exhibit resistance to 5-FU[90]. This occurs via the enzyme thymidylate synthase (TS), which functions as the target enzyme of 5-FU[89]. Overexpression is postulated to lead to reduced drug efficacy by providing an alternative pathway for DNA synthesis[90,91]. Dihydropyridine dehydrogenase (DPD) is another enzyme that plays a pivotal role in the catabolism of 5-FU, with its overexpression resulting in 5-FU degradation[92,93]. Furthermore, studies have demonstrated that tumors with deficient mismatch repair (dMMR) mechanisms are resistant due to an increased expression of TS and DPD, in comparison to proficient mismatch repair (pMMR) cells[94]. The enzymatic degradation of 5-FU via overexpressed DPD and the bypass mechanisms provided by elevated levels of TS reflect the dynamic interplay between drug efficacy and tumor survival strategies.
Activation of cellular survival pathways represents another dimension of 5-FU resistance. Notably, pathways such as PI3K/Akt, Wnt, and MAPK/ERK have been implicated in promoting cell survival and proliferation, enabling cancer cells to withstand the cytotoxic effects of 5-FU[95-97]. The activation of these pathways in response to 5-FU treatment underscores the adaptability of cancer cells, facilitating their survival in the face of therapeutic challenges. EMT has also been recognized as a key factor in 5-FU resistance[98,99]. In GIC, this process is associated with increased metastatic potential as it promotes tumor stemness and invasiveness.
Collectively, these mechanisms illustrate the intricate network of pathways contributing to 5-FU resistance in GIC. The insights garnered from understanding these resistance mechanisms are instrumental in the development of novel therapeutic strategies aimed at mitigating resistance and enhancing the efficacy of 5-FU-based treatments.
Breast carcinoma and resistance to HER-2 targeted therapies
When discussing difficult-to-treat solid tumors, it is essential that breast carcinoma (BC) is mentioned, as it is the most common malignancy affecting women in the United States[100]. HER-2-positive BC is a specific subtype of breast cancer characterized by overexpression of the HER2 protein[101]. The HER-2/neu (EGFR2 or ErbB2) is a transmembrane oncoprotein encoded by the HER2/neu gene and is a member of the family of RTKs that also includes EGFR (HER1, ErbB1), ErbB3, and ErbB4[102]. HER-2/neu is weakly detectable in epithelial cells of normal tissues but is overexpressed in approximately 20% to 25% of invasive breast cancers and has been linked to a poor prognosis and a high risk of cancer relapse[103]. Among FDA-approved HER2-targeted drugs are monoclonal antibodies (mAb), TKIs, and antibody-drug conjugates (ADC)[103-105]. Despite the benefits of anti-HER2 therapies in the survival rate of HER2 BC patients, unfortunately, it too follows the overarching theme of this manuscript.
Resistance is often acquired following initial treatment, with some patients being non-responsive from the start despite having the mutation of interest[102,103,106-108]. Acquired resistance to trastuzumab is often encountered in metastatic BC, making the search for clinically relevant mechanisms crucial to understanding how to prevent this event from occurring[108]. Trastuzumab is a monoclonal antibody that selectively targets the HER-2 receptor, an RTK overexpressed in approximately 20% of breast cancers[109]. By binding the extracellular domain (ECD) of HER2, trastuzumab blocks ligand-independent receptor dimerization, reduces downstream proliferative signaling (via PI3K/Akt and MAPK pathways), and enhances antibody-dependent cellular cytotoxicity (ADCC)[109]. Despite its efficacy, primary and acquired resistance to trastuzumab remain significant challenges. These resistance mechanisms include factors hindering trastuzumab binding to HER2; upregulation of HER2 downstream signaling pathways; and signaling through alternate pathways[110-116].
As suspected, one of the more common mechanisms of acquired resistance is receptor modification. More specifically, this resistance is characterized by p95HER2 overexpression[117]. p95HER2 is an amino terminally truncated membrane-bound fragment that is generated from the cleavage of the ECD following ligand binding[117]. High expression levels of p95HER2 make the cells resistant to trastuzumab as it cannot bind to p95HER2 due to ECD loss, which, unsurprisingly, is correlated with distant metastases and resultant decreased survival[117].
Upregulating downstream HER-2 signaling pathways is another mechanism in which BC can resist targeted therapy. Just as it is in other cancers, the RAS/Raf/MAPK and the PI3K/Akt cascades are the primary downstream signaling pathways in BC and play an important role in BC survival[118]. Specifically, loss-of-function PTEN deletions and activating mutations of PI3KCA, two of the most frequent genetic alterations in BC, cause increased activity of the PI3K/Akt pathway and can contribute to trastuzumab resistance[118].
While HER-2 is a key mediator of cell survival, there are other receptors (EGFR/HER1, HER3, and HER4) within the HER family that also have the potential to form dimers and mediate signaling[117]. Therefore, even with successful trastuzumab binding and inhibition, crosstalk still allows for the activation of alternative signaling pathways such as ER, IGF-1R, and HER3 signaling pathways[117]. For instance, IGF-1R is crucial in resistance and overexpressed in approximately 43%-50% of primary BC[117-119]. Aberrant activation of IGF-1R has been shown to upregulate the expression of the p27Kip1 ubiquitin ligase, SKP2[117-119]. This leads to the degradation of the cyclin-dependent kinase inhibitor (CDKI) p27Kip1, causing a loss of growth arrest[117-119]. Another example is HER3 acting as a crucial cofactor for sustaining cell proliferation in HER-2-overexpressing cell lines[120]. The heterodimerization of HER2 with HER3 activates the PI3K/Akt signaling pathway through the phosphorylation of HER3 receptors at multiple tyrosine residues[120]. The c-MET receptor and its ligand, HGF, further contribute to trastuzumab resistance by inhibiting trastuzumab-mediated p27 induction and continued Akt activation[120-122]. The increased expression of the receptor tyrosine kinase Eph receptor A2 (EphA2) has also been implicated in both intrinsic and acquired trastuzumab resistance[120-122].
In breast cancer, these alterations contribute to therapeutic resistance, especially in HER-2-positive subtypes treated with trastuzumab. The resistance mechanisms encompass not only direct alterations affecting HER2 but also downstream pathway modulations, further highlighting the complexities involved in treating resistant tumors[122].
Prostate carcinoma and androgen receptor resistance
PCa is the most common cancer in men, and there will be nearly 35,250 PCa-related estimated deaths in 2024, ranking second in cancer-related deaths in the United States[123-125]. Although most patients present with localized disease, progression to metastatic disease and its management remain significant clinical challenges. Most patients with advanced disease progress to metastatic castration-resistant prostate cancer (mCRPC), associated with a median OS of 4-5 years[126]. The prostate epithelium, as well as the cancerous cells, express high levels of AR, which encodes the androgen receptor (AR), and this has been associated with hormonal dependency in PCa[127]. The shift between an AR signal mainly associated with epithelial growth and differentiation to signaling associated with indiscriminate growth in the cancer scenario is unclear; nonetheless, although this AR pathway is the cornerstone of current therapies, resistance arises in the context of androgen deprivation therapy (ADT) and androgen blockade[128,129]. It is vital to note that AR activity is necessary for tumor development and is the primary driver of disease progression to the castration-resistant phase during ADT. The AR predominantly functions as a transcription factor in normal prostate homeostasis[130,131]. Genes such as KLK3, encoding prostate-specific antigen (PSA), are direct transcriptional targets of the AR, and their expression is often used as a surrogate for AR activity in PCa research and clinical monitoring[132]. The disease state is established where AR primarily drives a growth-related genetic program. Significantly, ADT is associated with alterations in the AR pathway, especially regarding AR overexpression and/or post-translation modifications that can lead to therapy resistance through multiple mechanisms. In this regard, most described mechanisms leading to castration resistance are mediated by AR or its related axis.
In mCRPC, for instance, there are increased mutations, amplifications of, and gain-of-function of AR. Amplification of the AR has been identified in up to 20% of mCRPC patients and is associated with response to the low levels of circulating and/or intra-tumor androgens[132]. It should also be noted that AR amplification is a unique characteristic of prostate tumors that have been exposed to androgen deprivation, indicating that AR amplification is a consequence of hormone therapy[133]. Reportedly, 70% of mCRPC patients have amplification or alterations of regulators for AR transcription, such as FOXA1[134]. Some genes that repress AR pro-tumorigenic signaling, like tumor suppressors ZBTB16 and NCOR1, have inactivating mutations or deletions[130,131]. By contrast, for metastatic castration-sensitive PCa, follow-up targeted genetic studies in matched samples of patients who later displayed progression onto mCRPC have shown that AR is altered in only 2%-6%, suggesting an acquired role for AR amplifications and mutations in mCRPC.
There are also reports of enhancers and regulators that have the potential to increase the expression of the AR gene independently of AR locus amplification in response to ADT[135]. In metastatic PCa, ADT has been associated with a mechanism of increased sensitivity to circulating androgens. A substitution of valine with leucine at codon 89, which is associated with more aggressive and early-onset PCa, has also been associated with increased 5α-reductase levels in a subset of mCRPC patients, rendering this population with higher levels of DHT despite low circulating levels of testosterone[135]. The substitution of threonine with alanine at codon 877 on the ligand binding domain of the AR, as well as L701H, V715M, and W741C substitutions, are among point mutations identified in the AR gene that lead to increased AR activity in the presence of low levels of androgens as well as non-androgenic steroids, such as hydrocortisone and estradiol.
There are also several AR co-activators, such as SRC1, SRC2, SRC3, ARA70, and PIAS1, that can interact with the AR and subsequently enhance its activity[136,137]. The key AR regulators, TIF2 and SRC1, have been associated with higher expression levels following androgen deprivation and are overexpressed in mCRPC samples. For instance, TIF2 enhances the AR transcriptional activation in response to adrenal androgens (DHEA and androstenedione)[138].
Identifying androgen receptor variants (AR-Vs) in tumors derived from mCRPC patients provides further mechanistic insight into the CRPC phenotype development[139,140]. AR-Vs are splice variants of AR that are constitutively active due to the loss of the C-terminal LBD. Significantly, treatment-induced AR amplification in CRPC may contribute to developing receptor variants. In a recent report, a 48-kb deletion in AR intron 1 was linked to the expression of the AR-V7/AR3 splice variant in the CWR-R1 cell line. After AR blockade with enzalutamide, the AR-V7/AR3-expressing clone was associated with tumor growth during ADT, providing mechanisms of AR splice variants in the pathogenesis of CRPC[139,140].
Pancreatic cancer and resistance to KRAS-targeted therapies
To date, pancreatic cancer remains one of the most challenging malignancies to treat, with a 5-year survival rate approaching 13%. In PAAD, the KRAS mutation is understood to be an early driver of tumorigenesis, as it is mutated in around 90%-95% of cases[141]. These mutations usually occur at the G12 site, with the G12D and G12V mutations making up 39.2% and 32.5% of alterations, respectively, followed by G12R and G12C at 17.1% and 1.7%[142].
The resultant effect is continual activation of KRAS downstream signaling, which promotes cancer cell growth and proliferation[143]. Aside from tumor intrinsic effects, mutant KRAS is also known to cultivate a proinflammatory and immunosuppressive environment by causing increased levels of TGFβ and IL-10 in the TME[144]. Additionally, in vivo studies demonstrated that KRAS mutation can drive highly mesenchymal subclones of PAAD cells that exhibit increased drug resistance[145]. Heterogeneity-driven resistance of PAAD is not just limited to varying states of EMT. The many parallel and redundant pathways branching off KRAS that drive cell survival and growth cause the effectiveness of KRAS inhibition to be highly context-dependent and subject to non-genetic acquired mechanisms of resistance.
The combination of all these effects from mutant KRAS primes the target to resist targeted therapies against it. This resistance is further compounded by the fibrotic nature and low vascularity of PAAD tumors, alongside a highly immunosuppressive TME[146]. This can create a formidable barrier against therapeutic interventions aimed at curbing tumor growth. However, the main reason underlying this tumor’s challenging target involves the dynamic and redundant signaling pathways activated by KRAS mutations. For instance, although ERK inhibition will reduce MAPK signaling in the short term, the drug-induced loss of the endogenous negative feedback capability eventually leads to MAPK activation rebounding to a new steady state, preventing a durable drug response[147]. A further factor limiting the effectiveness of inhibiting nonmutated proteins of the KRAS effector pathways is that therapies are not selective to mutant KRAS PAAD cells, substantially narrowing the therapeutic window due to toxic effects on normal physiological processes[142].
OvCa and resistance to poly (ADP-ribose) polymerase inhibitors
Despite advances in understanding the biology underpinning OvCa in the last decade, with an annual burden of 300,000 new cases, it continues to be the major cause of gynecological cancer-related deaths globally and the eight-leading cause of cancer deaths in women[148-150]. In most patients, OvCa tends to be diagnosed at an advanced stage, which, in combination with its heterogeneous molecular makeup, lends to its high mortality rate[151-153]. In 2023, the United States had an estimated 13,270 OvCa-related deaths and 5-year survival outcomes of around 30%-50%, depending on the stage at diagnosis[149]. The most common histological subtype of epithelial OvCa is high-grade serous ovarian cancer (HGSOC), which accounts for 60%-80% of all cases[148]. The mainstay of treatment is cytoreductive surgical debulking and platinum- or taxane-based chemotherapeutic regiments. Maintenance therapy typically includes VEGF inhibitors such as bevacizumab or, more recently, poly (ADP-ribose) polymerase inhibitors (PARPi). Some strategies to overcome PARP inhibitor resistance have been suggested[154-157].
PARPs are some of the best-known components of the DNA damage response (DDR)[158]. They detect single-strand breaks (SSBs) and recruit additional repair factors through poly-ADP ribosylation (PARylation) of target proteins, including chromatin-associated proteins[158]. By inhibiting PARP activity, PARPi prevent the repair of SSBs, leading to the accumulation of double-strand breaks and synthetic lethality in tumors with defective homologous recombination repair (HRR) (e.g., BRCA1/2-mutant cancers)[158]. HGSOC are under immense DNA replication stress and rely on DNA HRR via tumor suppressors such as BRCA1 and BRCA2 to maintain chromosomal stability. PARPi take advantage of this dependency by binding the active site of PARP, inhibiting its catalytic activity and trapping the PARP-DNA complex and destabilizing replication forks[159,160]. Initially approved for maintenance treatment of recurrent platinum-sensitive BRCA1/2 mutant epithelial OvCa, PARPi have shown benefits beyond these indications for HGSOC[161]. Despite all these advances, treatment-induced acquired resistance arises, which erodes the efficacy of these agents. Acquired resistance can be attributed to increased drug efflux from overexpression of multidrug efflux proteins, upregulation of survival pathways, and downregulation of DNA damage repair mechanisms[162]. Efflux proteins utilize ATP pumps to actively pump out the drug molecules before they can exert their effects intracellularly. The most notable examples are the adenosine triphosphate-binding cassette superfamily[163].
Activation of alternate oncogenic pathways such as PI3K/Akt/mTOR and RAF/MEK have also been described as potential mechanisms for resistance to PARPi due to the PARP-PI3K-Akt crosstalk with HRR. Preclinical studies show increased activation of the PI3K-Akt pathway in the setting of PARPi, inducing apoptosis resistance and limiting the cytostatic efficacy of PARPi[164]. Due to its regulation of key cellular processes including metabolism, motility, and growth, it stands to reason why PI3K/Akt/mTOR dysregulation leads to the aberrant proliferation of cancer cells.
A wide array of genomic alterations has been described involving PIK3CA, PTEN, AKT, TSC1, LKB1, and MTOR[165]. Early phase studies showed promising activity using a combination of a pan-PI3K inhibitor (buparlisib) and MEK inhibitor (trametinib) to overcome resistance in patients with low-grade serous OvCa with refractory RAS or RAF mutations and yielded an ORR of 29%. However, a significant portion of the patients had grade 3/4 AEs, including transaminitis, creatinine kinase elevation, and rash, which might limit the future utility of these agents in combination therapy[165-167].
A potential clinical predictive marker for PARPi resistance may be sensitivity to platinum-based chemotherapy. In HGSOC, both drug classes target DNA repair via pathways that likely share resistance commonalities such as secondary BRCA reversion mutations, loss of 53BP1, and replication fork protection[168-170]. Resistance to PARPi gives rise to dependence on other DNA repair pathways, leading to additional therapeutic opportunities. Since TP53 is almost ubiquitously lost in HGSOC, it points toward increased oncogenic stress. Ataxia telangiectasia and Rad3-related kinase (ATR) is a well-known regulator of cell death and controls cell cycle arrest from the S to G2 phases. In cells with TP53 mutation, ATR promotes checkpoint-defective cells, and the inhibition of this target may prove synthetically lethal[159,171,172]. Overcoming acquired resistance in OvCa will take combination therapy for continued improvements. The combination of PARPi and ATRi has shown a synergistic effect in terms of DNA damage and durable tumor regression. The CAPRI trial evaluated the combination of Olaparib and ceralasertib in platinum-sensitive HR-deficient HGSOC, which progressed on prior PARPi and had an ORR of 46%
Glioblastoma and treatment resistance
WHO grade IV, IDH-WT astrocytoma (GBM) is the most common aggressive form of primary brain cancer[180]. The development of targeted therapies for GBM has been significantly challenged by the complex mechanisms of resistance inherent to the tumor’s biology.
One of the primary treatment challenges in treating GBM is the blood-brain barrier (BBB), a network of endothelial cells, pericytes, and astrocytic foot processes that prevent many therapeutic compounds from entering the brain[181,182]. Even though the integrity of this network is relatively compromised in GBM, the aberrant features of GBM allow for the formation of the blood-brain tumor barrier (BBTB)[181,182]. While more permeable to circulating nutrients that the tumor needs, drug delivery remains an issue owing to an upregulation of efflux transporters such as MDR1 and P-glycoprotein that expel drug molecules[183-185]. Mechanical disruption methods like osmotic disruption and focused ultrasound have been attempted to enhance drug delivery through these barriers; however, these strategies have had limited success due to ineffectiveness or an unacceptable level of toxicity[186,187]. To date, nanocarriers and peptide-based drug delivery methods are being explored to improve penetration across this barrier, but more research is needed to validate the long-term efficacy and safety[188,189].
A major obstacle in treating GBM is the profound intra- and intergenetic heterogeneity. Because of this, effective targeted therapies are difficult to develop as treatments may only be effective against a specific subtype of cells, leading to recurrence following treatment as the resistant (non-targeted) cell populations continue to proliferate[190-192]. While there are several signaling pathways that are implicated in GBM pathogenesis, the Cancer Genome Atlas (TCGA) identified the RTK/RAS/PI3K, p53, and Rb pathways as foundational to GBM development[193]. As such, genetic alterations in these pathways contribute significantly to treatment resistance as crosstalk allows for the upregulation of downstream elements even in the presence of highly specific inhibitors. This is evident from the limited success of EGFR inhibitors despite the high prevalence of EGFR amplifications (including the unique variant EGFRvIII) in GBM[194,195]. In a similar fashion, the PI3K/Akt/mTOR pathway is also frequently activated in GBM, but is difficult to target due to redundancy with other signaling pathways and poor penetration across the BBB[196]. These pathways do not function in isolation; instead, they interact and compensate for one another.
Along with redundancy, these tumors also have developed specific resistance mechanisms to various agents. The most well-known is the developed resistance to the alkylating agent temozolomide (TMZ). TMZ acts by methylating guanine nucleosides, which nicks DNA and leads to apoptosis due to the inability to repair the damaged DNA[197]. However, when the DNA repair enzyme O6-methylguanine (O6-MeG)-DNA methyltransferase (MGMT) is active, it specifically reverses this action and renders TMZ ineffective[191,198].
Epigenetic silencing plays a role in keeping this protein at bay; however, once TMZ therapy is initiated, the tumor undergoes genetic remodeling, leaving the MGMT promoter region unmethylated and promoting tumoral resistance[191,198]. While this mechanism is the main cause of drug resistance in the therapy of recurrent GBM, other mechanisms such as MMR deficiencies can also contribute to TMZ resistance. When the MGMT enzyme is absent during DNA replication, the DNA polymerase enzyme incorrectly inserts thymine at the site of O6-MeG, which initiates the formation of the MMR complex[199,200]. Although not directly cytotoxic, the O6-MeG lesion induces cellular toxicity due to MMR complex recognition and processing, triggering cell death either by futile cycling or direct signaling[201].
Glioma-initiating cells (GICs) can also play a role in resistance in GBM. These cells reside in the hypoxic core of these tumors, where they contribute to resistance to radiotherapy via the kinases Chk1 and Chk2[202,203]. These kinases are activated in response to DNA damage signals, and their activity results in reduced sensitivity to radiation therapy[204,205]. GICs also express ABC at higher rates, which function as another obstacle for different therapies. Specifically, in GICs, hypoxia leads to upregulation of ABCC1 and ABCB1, promoting resistance to targeted therapies[206]. Hypoxia can also complicate matters as it both promotes the growth of GICs and upregulates hypoxia-inducible factor 1 (HIF-1), which has many downstream tumorigenic pathways[206,207]. Hypoxia-induced autophagy is a mechanism GICs use to survive under stress, which doubles as a resistance mechanism to these tumors. There are promising results showing that by inhibiting this specific autophagy in GICs with agents like chloroquine, sensitivity to TMZ is increased[206,208-210].
EMERGING STRATEGIES TO OVERCOME RESISTANCE
Throughout this discussion, we have delved into the myriad ways through which both solid and hematologic tumors develop resistance to targeted therapies. It is clear there are considerable overlaps in the adaptations these tumors employ, shedding light on the intricate struggle against cancer resistance. Equally as important, however, is looking at the various strategies employed to overcome these hurdles.
Synthetic lethality and exploiting genetic vulnerabilities
Synthetic lethality [Figure 2] explains a scenario where alterations in two specific genes simultaneously lead to cell death[211]. Cancer cells possessing a mutation in only one of a particular pair of genes may rely on the unmutated partner gene to survive. Targeting and disrupting the activity of this unmutated partner gene could result in the death of the cancer cells. Investigating the concept of synthetic lethality offers insights into gene function and aids in the creation of novel cancer therapies. For example, in NSCLC, overcoming resistance to EGFRi can be approached through synthetic lethality by targeting the NF-κB pathway[212,213]. Some studies highlight the role of NF-κB in promoting resistance to EGFRi treatment, showing that silencing specific genes related to the NF-κB and Fas death receptor signaling pathways can sensitize NSCLC cells to erlotinib[212,213]. The introduction of PBS-1068, an inhibitor targeting the RELA subunit of NF-κB, demonstrates promising results in not only enhancing the response to erlotinib but also inducing apoptosis in both intrinsic and acquired EGFRi resistance scenarios[213].
Figure 2. Exploitation of synthetic lethality in cancer therapy. The concept of synthetic lethality is represented along with examples of its clinical or experimental use in cancer therapy. Created in BioRender. Purcell, C. (2025) https://BioRender.com/hbbdh35.
Adaptive and dynamic therapy approaches
Overcoming acquired resistance to MTTs will require a paradigm shift from linear, single-agent treatments to adaptive, dynamic therapeutic strategies. One promising avenue is the application of adaptive therapy, which intentionally cycles drugs or adjusts dosing to prevent resistant clones from gaining dominance[214]. This approach leverages the concept of competitive suppression, wherein sensitive tumor cells keep resistant clones in check, effectively turning tumor heterogeneity into a therapeutic advantage (CUSP9 protocol)[215,216].
Simultaneously, advances in multiomic profiling - integrating genomics, transcriptomics, epigenomics, and proteomics - will allow clinicians to map the evolving resistance landscape in real time, guiding treatment modifications based on the tumor’s shifting vulnerabilities[217]. This personalized “resistance fingerprinting” could transform therapeutic decision making, shifting from reactive to proactive resistance management.
Targeting TME and non-oncogene dependencies
Beyond established targets, the future will also emphasize non-oncogene dependencies - exploiting metabolic bottlenecks, stress response pathways, and epigenetic vulnerabilities that emerge specifically in resistant cells[217]. Drugs targeting CAF signaling, exosome biogenesis, or tumor metabolic crosstalk may work synergistically with targeted therapies to block resistance-enabling interactions within the TME[218,219].
One example of targeting the TME is the inhibition of Tie2-expressing monocytes, which has been shown to impair tumor angiogenesis and progression[220]. Another approach is the use of tasquinimod, which inhibits MDSCs and angiogenesis within the TME, demonstrating the potential of disrupting non-oncogenic pathways to counteract resistance[221].
Next-generation molecularly targeted agents
Next-generation molecularly targeted agents will be engineered not only to inhibit driver pathways but also to anticipate common resistance mutations, incorporating elements of induced synthetic lethality to exploit vulnerabilities that arise only after resistance emerges. These future agents will likely combine multi-target inhibition with context-dependent activation to selectively disable both primary oncogenic drivers and the adaptive pathways that resistant cells rely on for survival[222,223].
A prime example of next-generation targeted therapy is the development of Hedgehog pathway inhibitors such as vismodegib and sonidegib, which are designed to block a key signaling pathway implicated in tumor progression and therapy resistance[224].
Together, these approaches represent a necessary evolution from static, pathway-centered therapy to dynamic, system-aware intervention, where therapy itself adapts in parallel with the evolving tumor.
CONCLUSION
Although much progress has been made in unraveling tumor biology, developing models, analyzing human tumor tissues at high resolution, defining cancer hallmarks, and devising novel therapeutic strategies, significant challenges remain in prolonging survival or curing more cancers. In the United States alone, each year, there are more than 600,000 cancer-related deaths despite all the advancements in research and treatment[1]. The complexity of tumor and host heterogeneity, along with the evolutionary dynamics of tumor adaptation, presents an ongoing challenge in the field. Tumors constantly evolve under selection pressure imposed by therapy, leading to resistance mechanisms that necessitate the development of multifaceted approaches[225].
The interplay between tumor microenvironmental factors, immune evasion, and metabolic reprogramming further complicates treatment strategies. Understanding these ecological and evolutionary dynamics not only presents obstacles but also provides opportunities for novel therapeutic interventions[226,227]. Another significant barrier remains the toxicity of cancer therapies, both in physiological and financial terms, which limit accessibility and tolerability for many patients[228].
Future research directions must integrate a holistic approach that acknowledges the complexity of the TME, the evolving resistance mechanisms, and the heterogeneity of cancer[228]. Advancements in precision oncology will continue to drive highly individualized treatment strategies, leveraging adaptive resistance-targeting therapies such as synthetic lethality-based interventions and real-time multiomic profiling. The next phase of drug development must incorporate therapies that anticipate resistance mutations and dynamically adapt to the evolving tumor landscape[229,230].
Moving forward, a dynamic and system-aware treatment paradigm is required - one that embraces continuous adaptation and innovation in oncology. This will necessitate interdisciplinary collaborations, novel computational and genomic methodologies, and the sustained refinement of precision medicine strategies to ultimately improve patient outcomes in the battle against acquired resistance.
DECLARATIONS
Acknowledgments
El-Deiry WS is an American Cancer Society Research Professor and is supported by the Mencoff Family University Professorship at Brown University.
Authors’ contributions
Conceptualization, methodology, validation, data curation, writing - original draft, writing - review and editing, visualization, project administration: Stubbs NM
Conceptualization, supervision, project administration, writing - review and editing, funding acquisition: El-Deiry WS
Investigation, data curation, writing - original draft, visualization: Roady TJ, Schwermann MP, Eteshola EO, MacDonald WJ, Purcell C, Ryspayeva D, Verovkina N, Tajiknia V, Ghandali M, Voong V, Lannigan AJ
Investigation, resources, writing - review and editing, supervision: Raufi AG, Lawler S, Holder SL, Carneiro BA, Cheng L, Safran HP, Graff SL, Dizon DS, Mani SA, Seyhan AA, Sobol RW, Wong ET, Chen CC, Gokaslan Z, Taylor MS
Writing - review and editing, funding acquisition: Rivers BM
Availability of data and materials
Not applicable.
Financial support and sponsorship
This work was supported by the Fostering Innovation Grant from the American Cancer Society to El-Deiry WS (ACS FIA-22-002-01-FIA “FIA-Morehouse School of Medicine and the Legorreta Cancer Center at Brown University). The ACS played no role in deciding the subject of the review or any of its citations.
Conflicts of interest
El-Deiry WS and Cheng L are Editorial Board members of the journal Cancer Drug Resistance. They were not involved in any steps of editorial processing, notably including reviewer selection, manuscript handling, or decision making. The other authors declared that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2025.
REFERENCES
1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209-49.
2. Wild CP, Weiderpass E, Stewart BW. World Cancer Report: cancer research for cancer prevention. Available from: https://publications.iarc.fr/586. [Last accessed on 26 May 2025].
3. Joko-Fru WY, Miranda-Filho A, Soerjomataram I, et al. Breast cancer survival in sub-Saharan Africa by age, stage at diagnosis and human development index: a population-based registry study. Int J Cancer. 2020;146:1208-18.
4. Prager GW, Braga S, Bystricky B, et al. Global cancer control: responding to the growing burden, rising costs and inequalities in access. ESMO Open. 2018;3:e000285.
5. Zhong L, Li Y, Xiong L, et al. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Signal Transduct Target Ther. 2021;6:201.
6. Housman G, Byler S, Heerboth S, et al. Drug resistance in cancer: an overview. Cancers. 2014;6:1769-92.
7. Luqmani YA. Mechanisms of drug resistance in cancer chemotherapy. Med Princ Pract. 2005;14 Suppl 1:35-48.
8. Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2010;1805:105-17.
9. Bray F, Laversanne M, Weiderpass E, Soerjomataram I. The ever-increasing importance of cancer as a leading cause of premature death worldwide. Cancer. 2021;127:3029-30.
10. Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004;4:937-47.
11. Kovalski JR, Bhaduri A, Zehnder AM, et al. The functional proximal proteome of oncogenic ras includes mTORC2. Mol Cell. 2019;73:830-44.e12.
12. Rizos H, Menzies AM, Pupo GM, et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res. 2014;20:1965-77.
13. Montagut C, Sharma SV, Shioda T, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68:4853-61.
14. Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968-72.
15. Shi H, Moriceau G, Kong X, et al. Melanoma whole-exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun. 2012;3:724.
16. Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal. 2010;3:ra84.
17. Ligresti G, Militello L, Steelman LS, et al. PIK3CA mutations in human solid tumors: role in sensitivity to various therapeutic approaches. Cell Cycle. 2009;8:1352-8.
19. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170:605-35.
20. Candido S, Salemi R, Piccinin S, Falzone L, Libra M. The PIK3CA H1047R mutation confers resistance to BRAF and MEK inhibitors in A375 melanoma cells through the cross-activation of MAPK and PI3K-Akt pathways. Pharmaceutics. 2022;14:590.
21. Shi H, Hugo W, Kong X, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014;4:80-93.
22. Muñoz-Couselo E, Adelantado EZ, Ortiz C, García JS, Perez-Garcia J. NRAS-mutant melanoma: current challenges and future prospect. Onco Targets Ther. 2017;10:3941-7.
23. Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell. 2012;150:251-63.
24. Mandalà M, Merelli B, Massi D. Nras in melanoma: targeting the undruggable target. Crit Rev Oncol Hematol. 2014;92:107-22.
25. Abel EV, Basile KJ, Kugel CH 3rd, et al. Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. J Clin Invest. 2013;123:2155-68.
26. Kun E, Tsang YTM, Ng CW, Gershenson DM, Wong KK. MEK inhibitor resistance mechanisms and recent developments in combination trials. Cancer Treat Rev. 2021;92:102137.
27. Wagle N, Van Allen EM, Treacy DJ, et al. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov. 2014;4:61-8.
28. Oda K, Matsuoka Y, Funahashi A, Kitano H. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol. 2005;1:2005.0010.
29. Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 2012;13:283-96.
30. Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer. 2012;12:159-69.
31. Gallagher EJ, LeRoith D. The proliferating role of insulin and insulin-like growth factors in cancer. Trends Endocrinol Metab. 2010;21:610-8.
32. Zhao S, Xue H, Hao CL, Jiang HM, Zheng HC. BTG1 overexpression might promote invasion and metastasis of colorectal cancer via decreasing adhesion and inducing epithelial-mesenchymal transition. Front Oncol. 2020;10:598192.
33. Correia AL, Bissell MJ. The tumor microenvironment is a dominant force in multidrug resistance. Drug Resist Updat. 2012;15:39-49.
34. Son B, Lee S, Youn H, Kim E, Kim W, Youn B. The role of tumor microenvironment in therapeutic resistance. Oncotarget. 2017;8:3933-45.
35. Ge R, Wang Z, Cheng L. Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance. NPJ Precis Oncol. 2022;6:31.
36. Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008;8:618-31.
37. Santoni M, Massari F, Amantini C, et al. Emerging role of tumor-associated macrophages as therapeutic targets in patients with metastatic renal cell carcinoma. Cancer Immunol Immunother. 2013;62:1757-68.
38. Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704-15.
39. Kuburich NA, Sabapathy T, Demestichas BR, Maddela JJ, den Hollander P, Mani SA. Proactive and reactive roles of TGF-β in cancer. Semin Cancer Biol. 2023;95:120-39.
40. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12:253-68.
41. Beury DW, Parker KH, Nyandjo M, Sinha P, Carter KA, Ostrand-Rosenberg S. Cross-talk among myeloid-derived suppressor cells, macrophages, and tumor cells impacts the inflammatory milieu of solid tumors. J Leukoc Biol. 2014;96:1109-18.
42. Shiga K, Hara M, Nagasaki T, Sato T, Takahashi H, Takeyama H. Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers. 2015;7:2443-58.
43. Kaur A, Webster MR, Marchbank K, et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature. 2016;532:250-4.
44. Wu F, Yang J, Liu J, et al. Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer. Signal Transduct Target Ther. 2021;6:218.
45. Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015;15:25-41.
46. Paraiso KH, Smalley KS. Fibroblast-mediated drug resistance in cancer. Biochem Pharmacol. 2013;85:1033-41.
47. Xavier CPR, Caires HR, Barbosa MAG, Bergantim R, Guimarães JE, Vasconcelos MH. The role of extracellular vesicles in the hallmarks of cancer and drug resistance. Cells. 2020;9:1141.
48. Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell. 2016;30:836-48.
49. Maleki S, Jabalee J, Garnis C. The role of extracellular vesicles in mediating resistance to anticancer therapies. Int J Mol Sci. 2021;22:4166.
50. Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367:eaau6977.
51. Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290-3.
52. Deininger MW, Shah NP, Altman JK, et al. Chronic myeloid leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18:1385-415.
53. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966-84.
54. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140:1200-28.
56. Bower H, Björkholm M, Dickman PW, Höglund M, Lambert PC, Andersson TM. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016;34:2851-7.
57. Radich JP, Deininger M, Abboud CN, et al. Chronic myeloid leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16:1108-35.
58. Hughes T, Saglio G, Branford S, et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol. 2009;27:4204-10.
60. Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017;543:733-7.
61. Neviani P, Harb JG, Oaks JJ, et al. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J Clin Invest. 2013;123:4144-57.
62. Ma L, Shan Y, Bai R, et al. A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia. Sci Transl Med. 2014;6:252ra121.
63. Mitchell R, Hopcroft LEM, Baquero P, et al. Targeting BCR-ABL-independent TKI resistance in chronic myeloid leukemia by mTOR and autophagy inhibition. J Natl Cancer Inst. 2018;110:467-78.
64. Terwilliger T, Abdul-Hay M. Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J. 2017;7:e577.
65. Mullighan CG, Goorha S, Radtke I, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007;446:758-64.
66. Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood. 2002;100:1965-71.
67. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038-42.
68. Jones CL, Gearheart CM, Fosmire S, et al. MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia. Blood. 2015;126:2202-12.
69. Verrills NM, Walsh BJ, Cobon GS, Hains PG, Kavallaris M. Proteome analysis of vinca alkaloid response and resistance in acute lymphoblastic leukemia reveals novel cytoskeletal alterations. J Biol Chem. 2003;278:45082-93.
70. Jabbour E, Short NJ, Jain N, et al. Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial. Lancet Haematol. 2023;10:E24-34.
71. Cortes JE, Kim DW, Pinilla-Ibarz J, et al; PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783-96.
72. Lipton JH, Chuah C, Guerci-Bresler A, et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17:612-21.
73. Alves R, Gonçalves AC, Rutella S, et al. Resistance to tyrosine kinase inhibitors in chronic myeloid leukemia - from molecular mechanisms to clinical relevance. Cancers. 2021;13:4820.
74. Advani AS, Forman SJ, Rowe JM. The role of ponatinib in Ph+ ALL: new strategies and future directions. Blood Adv. 2023;7:2412-21.
75. Rousselot P, Coudé MM, Gokbuget N. Combining ponatinib with blinatumomab: a chemotherapy-free strategy for Ph+ ALL. Haematologica. 2022;107:1394-403.
76. Cerovska E, Salek C, Kundrat D, et al. ABC transporters are predictors of treatment failure in acute myeloid leukaemia. Biomed Pharmacother. 2024;170:115930.
77. van Galen JC, Kuiper RP, van Emst L, et al. BTG1 regulates glucocorticoid receptor autoinduction in acute lymphoblastic leukemia. Blood. 2010;115:4810-9.
78. Hogan LE, Meyer JA, Yang J, et al. Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies. Blood. 2011;118:5218-26.
79. Nokin MJ, Ambrogio C, Nadal E, Santamaria D. Targeting infrequent driver alterations in non-small cell lung cancer. Trends Cancer. 2021;7:410-29.
80. Chevallier M, Borgeaud M, Addeo A, Friedlaender A. Oncogenic driver mutations in non-small cell lung cancer: past, present and future. World J Clin Oncol. 2021;12:217-37.
81. Johnson M, Garassino MC, Mok T, Mitsudomi T. Treatment strategies and outcomes for patients with EGFR-mutant non-small cell lung cancer resistant to EGFR tyrosine kinase inhibitors: focus on novel therapies. Lung Cancer. 2022;170:41-51.
82. Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4:1046-61.
83. Choi YL, Soda M, Yamashita Y, et al; ALK Lung Cancer Study Group. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010;363:1734-9.
84. Yang H, Wen L, Zhao C, et al. EGFR amplification is a putative resistance mechanism for NSCLC-LM patients with TKI therapy and is associated with poor outcome. Front Oncol. 2022;12:902664.
85. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4:120ra17.
86. Turke AB, Zejnullahu K, Wu YL, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010;17:77-88.
87. Sethy C, Kundu CN. 5-Fluorouracil (5-FU) resistance and the new strategy to enhance the sensitivity against cancer: Implication of DNA repair inhibition. Biomed Pharmacother. 2021;137:111285.
88. Das D, Preet R, Mohapatra P, et al. 5-Fluorouracil mediated anti-cancer activity in colon cancer cells is through the induction of Adenomatous Polyposis Coli: implication of the long-patch base excision repair pathway. DNA Repair. 2014;24:15-25.
89. Toriumi F, Kubota T, Saikawa Y, et al. Thymidylate synthetase (TS) genotype and TS/dihydropyrimidine dehydrogenase mRNA level as an indicator in determining chemosensitivity to 5-fluorouracil in advanced gastric carcinoma. Anticancer Res. 2004;24:2455-63.
90. Peters GJ, Backus HH, Freemantle S, et al. Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism. Biochim Biophys Acta. 2002;1587:194-205.
91. Verma H, Doshi J, Narendra G, Raju B, Singh PK, Silakari O. Energy decomposition and waterswapping analysis to investigate the SNP associated DPD mediated 5-FU resistance. SAR QSAR Environ Res. 2023;34:39-64.
92. Verma H, Narendra G, Raju B, Singh PK, Silakari O. Dihydropyrimidine dehydrogenase-mediated resistance to 5-fluorouracil: mechanistic investigation and solution. ACS Pharmacol Transl Sci. 2022;5:1017-33.
93. Wang WB, Yang Y, Zhao YP, Zhang TP, Liao Q, Shu H. Recent studies of 5-fluorouracil resistance in pancreatic cancer. World J Gastroenterol. 2014;20:15682-90.
94. He L, Zhu H, Zhou S, et al. Wnt pathway is involved in 5-FU drug resistance of colorectal cancer cells. Exp Mol Med. 2018;50:1-12.
95. Shi Z, Yu X, Yuan M, et al. Activation of the PERK-ATF4 pathway promotes chemo-resistance in colon cancer cells. Sci Rep. 2019;9:3210.
96. Dong S, Liang S, Cheng Z, et al. ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer. J Exp Clin Cancer Res. 2022;41:15.
97. Long S, Wang J, Weng F, et al. ECM1 regulates the resistance of colorectal cancer to 5-FU treatment by modulating apoptotic cell death and epithelial-mesenchymal transition induction. Front Pharmacol. 2022;13:1005915.
98. Ghosh S, Singh R, Vanwinkle ZM, et al. Microbial metabolite restricts 5-fluorouracil-resistant colonic tumor progression by sensitizing drug transporters via regulation of FOXO3-FOXM1 axis. Theranostics. 2022;12:5574-95.
99. Escalante PI, Quiñones LA, Contreras HR. Epithelial-mesenchymal transition and microRNAs in colorectal cancer chemoresistance to FOLFOX. Pharmaceutics. 2021;13:75.
100. Kim BH, Kwon J, Kim K. Evaluation of the benefit of radiotherapy in patients with occult breast cancer: a population-based analysis of the SEER database. Cancer Res Treat. 2018;50:551-61.
101. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127-37.
102. Martínez-Sáez O, Prat A. Current and future management of HER2-positive metastatic breast cancer. JCO Oncol Pract. 2021;17:594-604.
103. Rexer BN, Arteaga CL. Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit Rev Oncog. 2012;17:1-16.
104. Patel A, Unni N, Peng Y. The changing paradigm for the treatment of HER2-positive breast cancer. Cancers. 2020;12:2081.
105. Swain SM, Shastry M, Hamilton E. Targeting HER2-positive breast cancer: advances and future directions. Nat Rev Drug Discov. 2023;22:101-26.
106. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-92.
107. Rimawi MF, Schiff R, Osborne CK. Targeting HER2 for the treatment of breast cancer. Annu Rev Med. 2015;66:111-28.
109. Greenblatt K, Khaddour K. Trastuzumab. Treasure Island (FL): StatPearls Publishing; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532246/. [Last accessed on 26 May 2025].
110. Arribas J, Baselga J, Pedersen K, Parra-Palau JL. p95HER2 and breast cancer. Cancer Res. 2011;71:1515-9.
111. Scaltriti M, Rojo F, Ocaña A, et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99:628-38.
112. Miricescu D, Totan A, Stanescu-Spinu II, Badoiu SC, Stefani C, Greabu M. PI3K/AKT/mTOR signaling pathway in breast cancer: from molecular landscape to clinical aspects. Int J Mol Sci. 2020;22:173.
113. Pohlmann PR, Mayer IA, Mernaugh R. Resistance to trastuzumab in breast cancer. Clin Cancer Res. 2009;15:7479-91.
114. Dave A, Hernández ML, He Z, et al. 12-oxo-phytodienoic acid accumulation during seed development represses seed germination in Arabidopsis. Plant Cell. 2011;23:583-99.
115. Jensen MB, Ejlertsen B, Mouridsen HT, Christiansen P; Danish Breast Cancer Cooperative Group. Improvements in breast cancer survival between 1995 and 2012 in Denmark: the importance of earlier diagnosis and adjuvant treatment. Acta Oncol. 2016;55 Suppl 2:24-35.
116. Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6:117-27.
117. Elshazly AM, Gewirtz DA. An overview of resistance to Human epidermal growth factor receptor 2 (Her2) targeted therapies in breast cancer. Cancer Drug Resist. 2022;5:472-86.
118. Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395-402.
119. Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol. 2003;3:317-30.
120. Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011;29:4452-61.
121. Bosch A, Li Z, Bergamaschi A, et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci Transl Med. 2015;7:283ra51.
122. Juric D, Janku F, Rodón J, et al. Alpelisib plus fulvestrant in PIK3CA-altered and PIK3CA-wild-type estrogen receptor-positive advanced breast cancer: a phase 1b clinical trial. JAMA Oncol. 2019;5:e184475.
123. Freedland SJ, Davis M, Epstein AJ, Arondekar B, Ivanova JI. Real-world treatment patterns and overall survival among men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) in the US Medicare population. Prostate Cancer Prostatic Dis. 2024;27:327-33.
125. Gao X. Targeting androgen receptor mutations in metastatic castration-resistant prostate cancer with a novel androgen biosynthesis inhibitor. NEJM Evid. 2024;3:EVIDe2300298.
126. Goncharov AP, Vashakidze N, Kharaishvili G. Epithelial-mesenchymal transition: a fundamental cellular and microenvironmental process in benign and malignant prostate pathologies. Biomedicines. 2024;12:418.
127. Li X, Xiong H, Mou X, et al. Androgen receptor cofactors: a potential role in understanding prostate cancer. Biomed Pharmacother. 2024;173:116338.
128. Zengin ZB, Henderson NC, Park JJ, et al. Clinical implications of AR alterations in advanced prostate cancer: a multi-institutional collaboration. Prostate Cancer Prostatic Dis. 2024.
129. Wang L, Williamson SR, Zhang S, et al. Increased androgen receptor gene copy number is associated with TMPRSS2-ERG rearrangement in prostatic small cell carcinoma. Mol Carcinog. 2015;54:900-7.
130. Helminen L, Huttunen J, Tulonen M, et al. Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer. Nucleic Acids Res. 2024;52:625-42.
131. Quigley DA, Dang HX, Zhao SG, et al. Genomic hallmarks and structural variation in metastatic prostate cancer. Cell. 2018;174:758-69.e9.
132. Van-Duyne G, Blair IA, Sprenger C, Moiseenkova-Bell V, Plymate S, Penning TM. The androgen receptor. Vitam Horm 2023;123:439-81.
133. Saranyutanon S, Srivastava SK, Pai S, Singh S, Singh AP. Therapies targeted to androgen receptor signaling axis in prostate cancer: progress, challenges, and hope. Cancers. 2019;12:51.
134. Le TK, Duong QH, Baylot V, et al. Castration-resistant prostate cancer: from uncovered resistance mechanisms to current treatments. Cancers. 2023;15:5047.
135. Sun R, Yan B, Li H, et al. Androgen receptor variants confer castration resistance in prostate cancer by counteracting antiandrogen-induced ferroptosis. Cancer Res. 2023;83:3192-204.
136. Tilki D, Schaeffer EM, Evans CP. Understanding mechanisms of resistance in metastatic castration-resistant prostate cancer: the role of the androgen receptor. Eur Urol Focus. 2016;2:499-505.
137. Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 2013;73:483-9.
138. Karantanos T, Corn PG, Thompson TC. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene. 2013;32:5501-11.
139. Khan A, Mao Y, Tahreem S, Wei DQ, Wang Y. Structural and molecular insights into the mechanism of resistance to enzalutamide by the clinical mutants in androgen receptor (AR) in castration-resistant prostate cancer (CRPC) patients. Int J Biol Macromol. 2022;218:856-65.
140. Daniels VA, Luo J, Paller CJ, Kanayama M. Therapeutic approaches to targeting androgen receptor splice variants. Cells. 2024;13:104.
141. Bailey P, Chang DK, Nones K, et al; Australian Pancreatic Cancer Genome Initiative. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016;531:47-52.
143. Huang L, Guo Z, Wang F, Fu L. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Target Ther. 2021;6:386.
144. Gu M, Gao Y, Chang P. KRAS mutation dictates the cancer immune environment in pancreatic ductal adenocarcinoma and other adenocarcinomas. Cancers. 2021;13:2429.
145. Genovese G, Carugo A, Tepper J, et al. Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer. Nature. 2017;542:362-6.
147. Pratilas CA, Solit DB. Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response. Clin Cancer Res. 2010;16:3329-34.
148. Kandalaft LE, Dangaj Laniti D, Coukos G. Immunobiology of high-grade serous ovarian cancer: lessons for clinical translation. Nat Rev Cancer. 2022;22:640-56.
149. Veneziani AC, Gonzalez-Ochoa E, Alqaisi H, et al. Heterogeneity and treatment landscape of ovarian carcinoma. Nat Rev Clin Oncol. 2023;20:820-42.
150. Havasi A, Cainap SS, Havasi AT, Cainap C. Ovarian cancer-insights into platinum resistance and overcoming it. Medicina. 2023;59:544.
151. Webb PM, Jordan SJ. Global epidemiology of epithelial ovarian cancer. Nat Rev Clin Oncol. 2024;21:389-400.
152. McCluggage WG, Singh N, Gilks CB. Key changes to the World Health Organization (WHO) classification of female genital tumours introduced in the 5th edition (2020). Histopathology. 2022;80:762-78.
153. Shih IM, Wang Y, Wang TL. The origin of ovarian cancer species and precancerous landscape. Am J Pathol. 2021;191:26-39.
154. Mitri Z, Goodyear SM, Mills G. Strategies for the prevention or reversal of PARP inhibitor resistance. Expert Rev Anticancer Ther. 2024;24:959-75.
155. Prados-Carvajal R, Irving E, Lukashchuk N, Forment JV. Preventing and overcoming resistance to PARP inhibitors: a focus on the clinical landscape. Cancers. 2021;14:44.
156. Dias MP, Moser SC, Ganesan S, Jonkers J. Understanding and overcoming resistance to PARP inhibitors in cancer therapy. Nat Rev Clin Oncol. 2021;18:773-91.
157. Bhamidipati D, Haro-Silerio JI, Yap TA, Ngoi N. PARP inhibitors: enhancing efficacy through rational combinations. Br J Cancer. 2023;129:904-16.
158. Gourley C, Balmaña J, Ledermann JA, et al. Moving from poly (ADP-ribose) polymerase inhibition to targeting DNA repair and DNA damage response in cancer therapy. J Clin Oncol. 2019;37:2257-69.
159. Klotz DM, Wimberger P. Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies? Arch Gynecol Obstet. 2020;302:1087-102.
160. Topatana W, Juengpanich S, Li S, et al. Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation. J Hematol Oncol. 2020;13:118.
161. Miller RE, El-Shakankery KH, Lee JY. PARP inhibitors in ovarian cancer: overcoming resistance with combination strategies. J Gynecol Oncol. 2022;33:e44.
162. Alatise KL, Gardner S, Alexander-Bryant A. Mechanisms of drug resistance in ovarian cancer and associated gene targets. Cancers. 2022;14:6246.
163. Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 2001;11:1156-66.
164. Gallyas F Jr, Sumegi B, Szabo C. Role of Akt activation in PARP inhibitor resistance in cancer. Cancers. 2020;12:532.
165. Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol. 2018;15:273-91.
166. Bedard PL, Tabernero J, Janku F, et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin Cancer Res. 2015;21:730-8.
167. Farley J, Brady WE, Vathipadiekal V, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol. 2013;14:134-40.
168. Soberanis Pina P, Lheureux S. Overcoming PARP inhibitor resistance in ovarian cancer. Int J Gynecol Cancer. 2023;33:364-76.
169. Ang JE, Gourley C, Powell CB, et al. Efficacy of chemotherapy in BRCA1/2 mutation carrier ovarian cancer in the setting of PARP inhibitor resistance: a multi-institutional study. Clin Cancer Res. 2013;19:5485-93.
170. Cecere SC, Giannone G, Salutari V, et al. Olaparib as maintenance therapy in patients with BRCA 1-2 mutated recurrent platinum sensitive ovarian cancer: real world data and post progression outcome. Gynecol Oncol. 2020;156:38-44.
171. Ngoi NY, Sundararajan V, Tan DS. Exploiting replicative stress in gynecological cancers as a therapeutic strategy. Int J Gynecol Cancer. 2020;30:1224-38.
172. Wethington SL, Shah PD, Martin L, et al. Combination ATR (ceralasertib) and PARP (olaparib) inhibitor (CAPRI) trial in acquired PARP inhibitor-resistant homologous recombination-deficient ovarian cancer. Clin Cancer Res. 2023;29:2800-7.
173. Konstantinopoulos PA, Cheng SC, Wahner Hendrickson AE, et al. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21:957-68.
174. Westin SN, Labrie M, Litton JK, et al. Phase Ib dose expansion and translational analyses of olaparib in combination with capivasertib in recurrent endometrial, triple-negative breast, and ovarian cancer. Clin Cancer Res. 2021;27:6354-65.
175. Yap TA, Kristeleit R, Michalarea V, et al. Phase I trial of the PARP inhibitor olaparib and AKT inhibitor capivasertib in patients with BRCA1/2- and non-BRCA1/2-mutant cancers. Cancer Discov. 2020;10:1528-43.
176. Cristea MC, Stewart D, Synold T, et al. A phase I study of Mirvetuximab Soravtansine and gemcitabine in patients with FRα-positive recurrent ovarian, primary peritoneal, fallopian tube, or endometrial cancer, or triple negative breast cancer. Gynecol Oncol. 2024;182:124-31.
177. Zhou J, Gelot C, Pantelidou C, et al. A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nat Cancer. 2021;2:598-610.
178. Zatreanu D, Robinson HMR, Alkhatib O, et al. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat Commun. 2021;12:3636.
179. Zhang M, Wang J, Guo Y, Yue H, Zhang L. Activation of PI3K/AKT/mTOR signaling axis by UBE2S inhibits autophagy leading to cisplatin resistance in ovarian cancer. J Ovarian Res. 2023;16:240.
180. Hanif F, Muzaffar K, Perveen K, Malhi SM, Simjee SU. Glioblastoma multiforme: a review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev. 2017;18:3-9.
181. Ballabh P, Braun A, Nedergaard M. The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis. 2004;16:1-13.
182. Cheng L, Huang Z, Zhou W, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153:139-52.
183. Ueda K, Cornwell MM, Gottesman MM, et al. The mdr1 gene, responsible for multidrug-resistance, codes for P-glycoprotein. Biochem Biophys Res Commun. 1986;141:956-62.
184. Cole SP, Bhardwaj G, Gerlach JH, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science. 1992;258:1650-4.
185. Tsuji A, Terasaki T, Takabatake Y, et al. P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sci. 1992;51:1427-37.
186. Desjardins A, Gromeier M, Herndon JE 2nd, et al. Recurrent glioblastoma treated with recombinant poliovirus. N Engl J Med. 2018;379:150-61.
187. Chen KT, Lin YJ, Chai WY, et al. Neuronavigation-guided focused ultrasound (NaviFUS) for transcranial blood-brain barrier opening in recurrent glioblastoma patients: clinical trial protocol. Ann Transl Med. 2020;8:673.
188. Thomas E, Colombeau L, Gries M, et al. Ultrasmall AGuIX theranostic nanoparticles for vascular-targeted interstitial photodynamic therapy of glioblastoma. Int J Nanomedicine. 2017;12:7075-88.
189. Pandey V, Haider T, Chandak AR, Chakraborty A, Banerjee S, Soni V. Surface modified silk fibroin nanoparticles for improved delivery of doxorubicin: development, characterization, in-vitro studies. Int J Biol Macromol. 2020;164:2018-27.
190. Yang Z, Wei D, Dai X, et al. C8-substituted imidazotetrazine analogs overcome temozolomide resistance by inducing DNA adducts and DNA damage. Front Oncol. 2019;9:485.
191. Thon N, Kreth S, Kreth FW. Personalized treatment strategies in glioblastoma: MGMT promoter methylation status. Onco Targets Ther. 2013;6:1363-72.
192. Cabrini G, Fabbri E, Lo Nigro C, Dechecchi MC, Gambari R. Regulation of expression of O6-methylguanine-DNA methyltransferase and the treatment of glioblastoma (Review). Int J Oncol. 2015;47:417-28.
193. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061-8.
194. Weller M, Butowski N, Tran DD, et al; ACT IV trial investigators. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18:1373-85.
195. Hasselbalch B, Lassen U, Hansen S, et al. Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial. Neuro Oncol. 2010;12:508-16.
196. Schreck KC, Grossman SA, Pratilas CA. BRAF mutations and the utility of RAF and MEK inhibitors in primary brain tumors. Cancers. 2019;11:1262.
197. Wesolowski JR, Rajdev P, Mukherji SK. Temozolomide (Temodar). AJNR Am J Neuroradiol. 2010;31:1383-4.
198. Verbeek B, Southgate TD, Gilham DE, Margison GP. O6-Methylguanine-DNA methyltransferase inactivation and chemotherapy. Br Med Bull. 2008;85:17-33.
199. Erasimus H, Gobin M, Niclou S, Van Dyck E. DNA repair mechanisms and their clinical impact in glioblastoma. Mutat Res Rev Mutat Res. 2016;769:19-35.
200. Stritzelberger J, Distel L, Buslei R, Fietkau R, Putz F. Acquired temozolomide resistance in human glioblastoma cell line U251 is caused by mismatch repair deficiency and can be overcome by lomustine. Clin Transl Oncol. 2018;20:508-16.
201. Fujii S, Sobol RW, Fuchs RP. Double-strand breaks: when DNA repair events accidentally meet. DNA Repair. 2022;112:103303.
202. Dirkse A, Golebiewska A, Buder T, et al. Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment. Nat Commun. 2019;10:1787.
203. Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396-401.
204. Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756-60.
205. Uribe D, Torres Á, Rocha JD, et al. Multidrug resistance in glioblastoma stem-like cells: role of the hypoxic microenvironment and adenosine signaling. Mol Aspects Med. 2017;55:140-51.
206. Westover D, Li F. New trends for overcoming ABCG2/BCRP-mediated resistance to cancer therapies. J Exp Clin Cancer Res. 2015;34:159.
207. Walsh JC, Lebedev A, Aten E, Madsen K, Marciano L, Kolb HC. The clinical importance of assessing tumor hypoxia: relationship of tumor hypoxia to prognosis and therapeutic opportunities. Antioxid Redox Signal. 2014;21:1516-54.
208. Monteiro AR, Hill R, Pilkington GJ, Madureira PA. The role of hypoxia in glioblastoma invasion. Cells. 2017;6:45.
209. Hu YL, DeLay M, Jahangiri A, et al. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res. 2012;72:1773-83.
210. Sotelo J, Briceño E, López-González MA. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2006;144:337-43.
211. Nijman SM. Synthetic lethality: general principles, utility and detection using genetic screens in human cells. FEBS Lett. 2011;585:1-6.
212. Sudo M, Mori S, Madan V, Yang H, Leong G, Koeffler HP. Short-hairpin RNA library: identification of therapeutic partners for gefitinib-resistant non-small cell lung cancer. Oncotarget. 2015;6:814-24.
213. Blakely CM, Pazarentzos E, Olivas V, et al. NF-κB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep. 2015;11:98-110.
214. Zahir N, Sun R, Gallahan D, Gatenby RA, Curtis C. Characterizing the ecological and evolutionary dynamics of cancer. Nat Genet. 2020;52:759-67.
215. Wang L, Lankhorst L, Bernards R. Exploiting senescence for the treatment of cancer. Nat Rev Cancer. 2022;22:340-55.
216. Schmitt CA, Wang B, Demaria M. Senescence and cancer - role and therapeutic opportunities. Nat Rev Clin Oncol. 2022;19:619-36.
218. Gatenby RA, Brown JS. Integrating evolutionary dynamics into cancer therapy. Nat Rev Clin Oncol. 2020;17:675-86.
220. De Palma M, Lewis CE. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell. 2013;23:277-86.
221. Isaacs JT, Antony L, Dalrymple SL, et al. Tasquinimod is an allosteric modulator of HDAC4 survival signaling within the compromised cancer microenvironment. Cancer Res. 2013;73:1386-99.
222. Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science. 2017;355:1152-8.
223. O’Sullivan CC, Moon DH, Kohn EC, Lee JM. Beyond breast and ovarian cancers: PARP inhibitors for BRCA mutation-associated and BRCA-like solid tumors. Front Oncol. 2014;4:42.
224. Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo HW. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers. 2016;8:22.
225. Ngoi NYL, Gallo D, Torrado C, Nardo M, Durocher D, Yap TA. Synthetic lethal strategies for the development of cancer therapeutics. Nat Rev Clin Oncol. 2025;22:46-64.
226. Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501:346-54.
227. McGranahan N, Swanton C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell. 2017;168:613-28.
228. Sullivan R, Alatise OI, Anderson BO, et al. Global cancer surgery: delivering safe, affordable, and timely cancer surgery. Lancet Oncol. 2015;16:1193-224.
229. Bedard PL, Hansen AR, Ratain MJ, Siu LL. Tumour heterogeneity in the clinic. Nature. 2013;501:355-64.
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