Aug 2026· Frontiers in Cell and Developmental Biology· Vol 14· 0 citations· 181 references
Medicine
TL;DR
The persistent emergence of resistance underscores that current targeted therapies, while revolutionary, are primarily disease-modifying rather than curative, necessitating continuous innovation to overcome the inherent biological challenge of tumor adaptability and heterogeneity.
Abstract
Acquired resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a formidable challenge in the treatment of non-small cell lung cancer (NSCLC). Despite the remarkable efficacy of these agents, resistance inevitably develops, typically within approximately 10 months of treatment initiation. This review elucidates the multifaceted mechanisms driving this resistance, broadly categorized into on-target EGFR-dependent alterations and off-target EGFR-independent bypass pathway activations. On-target mechanisms include the emergence of tertiary EGFR mutations, most notably C797S, which disrupts TKI binding. Off-target mechanisms encompass the activation of alternative signaling pathways such as MET and HER2/HER3 amplification, as well as histological transformations and complex changes within the tumor microenvironment. Furthermore, recent discoveries highlight the role of epigenetic dysregulation and metabolic reprogramming in fostering resistance. To counter this pervasive adaptability, advanced diagnostic methodologies, including liquid biopsy and high-resolution omics technologies, are crucial for real-time molecular profiling. The field is actively exploring emerging combination therapeutic strategies to circumvent these diverse resistance pathways, aiming to prolong clinical benefits and improve patient outcomes. The persistent emergence of resistance underscores that current targeted therapies, while revolutionary, are primarily disease-modifying rather than curative, necessitating continuous innovation to overcome the inherent biological challenge of tumor adaptability and heterogeneity.
Tyrosine kinase inhibitors (TKIs) have significantly changed the treatment of non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations, and osimertinib is now established as first-line therapy for NSCLCs. Combination therapies (e.g., osimertininb plus chemotherapy; lazertinib plus amivantamab) have been shown to improve median progression-free survival (mPFS) and median overall survival (mOS) relative to monotherapy. However, due to several resistance mechanisms, patients experience disease progression following EGFR TKI treatment. On-target resistance mechanisms include additional mutations (e.g., C797S/G/N, L718Q, L844V, G724X). Within the heterogeneous group of off-target resistance mechanisms, human epidermal growth factor receptor 2 (HER2) amplifications, mesenchymal-epithelial transition factor (MET) alterations, oncogenic fusions (e.g., BRAF, FGFR, RET), histological changes, epithelial-mesenchymal transitions, and alterations of the RAS/MEK/ERK and the PI3K/AKT/mTOR signal transduction pathways are critical and can confer resistance to EGFR TKIs. Several drugs have been identified to inhibit these pathways, with some of them already approved for clinical use. Most fourth-generation EGFR TKIs are orally bioavailable and are mainly allosteric thiazole amide-based reversible inhibitors. Their activity results from selective binding to an allosteric site, which can alter the EGFR protein conformation, allowing them to bypass C797X. A recommendation for the optimal treatment strategy and sequence for NSCLC patients with acquired EGFR TKI-resistant tumours still cannot be given. An improved understanding of the underlying resistance mechanisms will help to pave the way for the development of innovative and highly specific drugs for the therapy of osimertinib-resistant NSCLCs. The putative clinical relevance of fourth-generation EGFR TKIs for NSCLC patients needs to be defined, and many development hurdles need to be cleared before victory can be declared.
W. Dempke, K. Fenchel, Loretta Sullivan et al.· Cancer Drug Resistance· 0 citations
Epidermal growth factor receptor (EGFR) mutations represent a central oncogenic driver in non-small cell lung cancer (NSCLC). While EGFR tyrosine kinase inhibitors (TKIs) have revolutionized the management of NSCLC, acquired resistance remains a major hurdle. In response, antibody-based therapeutic strategies have gained increasing attention as a means to overcome TKI resistance and extend disease control. This review synthesizes the rapidly evolving landscape of antibody-based therapeutics for EGFR-mutant NSCLC. We first summarize the mechanisms of monoclonal antibodies directly targeting EGFR, including cetuximab and necitumumab, and discuss their therapeutic limitations. We then highlight the emergence of bispecific antibodies designed to simultaneously target EGFR and key resistance pathways, such as MET. In addition, we review combination strategies integrating EGFR inhibition with antibodies directed against alternative oncogenic pathways or the tumor microenvironment, including anti-angiogenic agents such as bevacizumab. A major focus of this review is antibody-drug conjugates (ADCs) targeting novel surface antigens, including HER2, HER3, and TROP2. By delivering highly potent cytotoxic payloads selectively to tumor cells, these ADCs have demonstrated remarkable clinical efficacy in EGFR TKI-resistant settings. Furthermore, we examine the complex and evolving role of immunotherapy in EGFR-mutant NSCLC. Beyond immune checkpoint blockade, we discuss emerging immunomodulatory strategies targeting the adenosine pathway (CD73), phagocytosis checkpoints (CD24), and complement regulatory proteins (CD55/CD59). Finally, we explore advanced antibody modalities, including immune-engaging bispecific antibodies and next-generation ADCs. Collectively, antibody-based therapies are reshaping the treatment landscape through diverse mechanisms, offering renewed promise for overcoming resistance and improving outcomes in EGFR-mutant NSCLC.
Xin-Ran Chen, Jia-Qi Liang, Jun-Kan Zhu et al.· Biochimica et biophysica act...· 0 citations
RAS alterations mediate resistance to targeted agents in approximately 10% of oncogene-driven lung cancer, and Rational combinations with novel RAS inhibitors are effective in preclinical models, providing the basis for their clinical investigation and extending the paradigm of precision oncology.
F. Facchinetti, L. Friboulet, L. Liao et al.· Annals of Oncology· 0 citations
The epidermal growth factor receptor (EGFR) plays pivotal role in cancer promotion and progression, particularly in non-small cell lung cancer (NSCLC), where activating EGFR mutations drive tumour growth. Targeted therapies, such as tyrosine kinase inhibitors (TKIs), have improved patient survival rates, but resistance inevitably develops through mechanisms ranging from secondary mutations to bypass signalling pathways and histological transformation. A key factor in resistance development is the emergence of drug-tolerant persister cells, a rare population with epigenetic alterations that precede permanent, mutation-driven resistance. These cells evade apoptosis by triggering an evolutionarily conserved survival mechanism known as SOS. The SOS process is accompanied by increased reactive oxygen species, DNA breaks, defective DNA repair and activation of mutation-inducing factors like error-prone DNA polymerases and imbalanced dNTP pools. In patients receiving TKIs, this adaptive response probably drives the formation of extrachromosomal circular DNA and various genomic aberrations, collectively resembling chromothripsis. The aberrations include not only point mutations and gene amplifications but also indels and gene fusions. To overcome resistance, new therapeutic strategies are being explored, such as fourth-generation TKIs, allosteric inhibitors, degraders and bispecific antibodies. Ongoing research into EGFR biology offers the potential to transform EGFR-positive NSCLC from a lethal disease into a chronic, manageable condition. This article is part of the discussion meeting issue 'Epidermal growth factor receptor after 40 years'.
Arturo Simoni-Nieves, Marieke Van Daele, Harrison B. Konsker et al.· Philosophical transactions o...· 1 citation
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have transformed the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). However, the inevitable emergence of acquired resistance significantly limits their long-term efficacy. While conventional accounts of resistance have primarily focused on tumor-intrinsic genetic alterations, accumulating evidence highlights the pivotal role of the tumor microenvironment (TME) in mediating therapeutic failure. The TME contributes to EGFR-TKI resistance through multiple interconnected mechanisms, including immunosuppression, extracellular matrix-mediated physical barriers, metabolic reprogramming, and compensatory signaling activation. These complex interactions create a protective niche that enables tumor cells to persist despite EGFR inhibition. Traditional Chinese medicine (TCM), characterized by its multi-component and multi-target properties, offers a potential systems-level approach to modulating the TME. Preclinical studies suggest that TCM-derived interventions may influence immune-cell polarization, stromal and vascular features, and tumor metabolism, thereby affecting EGFR-TKI sensitivity. This review focuses on TME-mediated EGFR-TKI resistance in NSCLC and appraises TCM interventions according to evidence type and directness. We evaluate current preclinical and clinical evidence, identify major limitations, and propose priorities for translational research. The review provides a conceptual framework for evaluating TCM-based combination strategies intended to attenuate EGFR-TKI resistance.
Background Third-generation epidermal growth factor receptor tyrosine kinase inhibitor osimertinib serves as the gold standard therapy for treating NSCLC patients harboring EGFR T790M mutations. The clinical utility of this agent, however, faces considerable constraints due to the unavoidable emergence of acquired resistance mechanisms. Understanding the molecular basis of osimertinib resistance holds paramount importance for determining optimal follow-up treatment approaches. Methods Clinical information from 86 lung adenocarcinoma patients carrying EGFR T790M mutations who showed disease advancement following osimertinib therapy was examined retrospectively, spanning the period from January 2018 through December 2023. Genomic characterization was conducted via next-generation sequencing on tissue or liquid biopsy specimens collected after resistance developed. Protein expression alterations were assessed through immunohistochemical staining, while critical resistance pathways underwent validation using cell line models. Results Among the 86-patient cohort, the median duration before disease progression reached 14.2 months. Genomic characterization identified these predominant resistance pathways: C797S mutations in EGFR (23.3%), amplification of MET (15.1%), amplification of HER2 (8.1%), mutations in PIK3CA (7.0%), transformation to small cell lung cancer (9.3%), and epithelial-mesenchymal transition (12.8%). Concurrent presence of multiple resistance mechanisms was detected in 24.4% of the patient population. Within the C797S mutation subset, 65.0% exhibited C797S/T790M in cis arrangement, 30.0% demonstrated trans arrangement, and 5.0% showed mixed configurations. Laboratory validation established that MET amplification confers resistance via bypass activation of both ERK and AKT signaling cascades. The poorest clinical outcomes were observed among patients undergoing histological transformation (median overall survival from confirmed progression: 8.3 months). Conclusion Remarkable heterogeneity characterizes the resistance mechanisms emerging against osimertinib in EGFR T790M-positive lung adenocarcinoma, with EGFR secondary mutations, bypass signaling pathway activation, and histological transformation representing the primary categories. Detection of specific resistance mechanisms enables tailored subsequent therapeutic approaches, with potential outcome improvements achievable through combination strategies incorporating targeted agents or immunotherapy.
