Jul 2026· Current Medicinal Chemistry· Vol 33· 0 citations
Medicine
TL;DR
This review provides a comprehensive overview of EGFR biology, its signaling pathways, and strategies for therapeutic targeting and explores fourth-generation TKIs and allosteric inhibitors alongside newer treatment strategies, such as PROTACs, combination immunotherapy, and precision medicine methods.
Abstract
INTRODUCTION/
Objective
Regulation of cell growth, survival, and differentiation relies heavily on the epidermal growth factor receptor (EGFR). Dysregulations of EGFR signaling, whether due to overexpression or mutations, play a major role in the development of many cancers, particularly non-small cell lung cancer. In this review, we provide a comprehensive overview of EGFR biology, its signaling pathways, and strategies for therapeutic targeting.
Methods
This review combines the existing research on EGFR structure and its interactions with ligands, along with the signaling pathways that follow. It focuses on RAS/RAF/MEK/ERK and PI3K/AKT/mTOR axes, while considering JAK/STAT and PLCγ/PKC signaling. It alsofocuses on the triple mutant EGFR (L858R, T790M, and C797S) and discusses the therapeutic shift from first-generation reversible inhibitors to later generations of irreversible tyrosine kinase inhibitors. This review also examines a new wave of treatments. It explores fourth-generation TKIs and allosteric inhibitors alongside newer treatment strategies, such as PROTACs, combination immunotherapy, and precision medicine methods.
Results
For NSCLS patients with activating mutations, progress in EGFR-targeted treatments has transformed clinical outcomes. Due to the rise in resistance mechanisms, such as secondary mutations, the long-term effectiveness remains blocked. However, ongoing research on new treatment strategies reveals promising potential to overcome resistance and improve treatment effectiveness.
Discussion
Combining what we have learned about the EGFR at the molecular level with new therapeutic approaches highlights how valuable precision oncology has become in treating cancer. To improve treatment outcomes, we need to understand how pathways, mutations, and drug response interact with each other.
Conclusion
In this review, we aim to outline current knowledge and future directions in EGFR-targeted therapy by providing insights into newer strategies and precision oncology.
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.
Gu-Ha A-Lai, Lian Li, G. Ma et al.· Frontiers in Cell and Develo...· 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
Regulation of cancer cells by their environment contributes to tumorigenesis and drug response, though the extent to which the oncogenic state can alter a cell's perception of its environment is not clear. EML4-ALK is a receptor tyrosine kinase (RTK) fusion oncoprotein that suppresses transmembrane EGFR signaling in cancer cells. ALK inhibition restores signaling through EGFR, thereby promoting survival and drug tolerance. Here, we tested whether such modulation of EGFR activity was common among other RTK fusions, which collectively are found in ~5% of all cancers. Using live- and fixed-cell microscopy in isogenic and patient-derived cell lines, we found that a wide variety of RTK fusions suppress transmembrane EGFR, through mechanisms that include the sequestration of the adaptor protein Grb2. Targeted therapies rapidly released Grb2 from sequestration and potentiated EGFR. Synthetic optogenetic analogs of RTK fusions confirmed that cytoplasmic sequestration of Grb2 was sufficient to suppress perception of extracellular EGF and could do so without driving signaling from the synthetic fusion itself, demonstrating that fusion signaling and suppression of EGFR signaling could be functionally decoupled. Our study uncovers that a large number of RTK fusions simultaneously act as both activators and suppressors of signaling, the mechanisms of which could be exploited for biomimetic therapies that enhance cell killing and suppress drug tolerance.
Y. Gao, D. Gonzalez-Martinez, Sofia Wissert et al.· Proceedings of the National...· 0 citations
PIK3CA, which encodes the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), is one of the most frequently altered oncogenes in human cancer and a major driver of tumor initiation, progression, metastasis, and therapeutic resistance. Over the past two decades, advances in structural biology, cancer genomics, and translational research have substantially expanded our understanding of PIK3CA function and established the PI3K pathway as a clinically actionable therapeutic target. This review provides an overview of the structural organization and physiological functions of the PI3Kα complex, the molecular mechanisms underlying oncogenic activation, and the diverse spectrum of PIK3CA alterations across human malignancies. We also summarize the current landscape of PI3K-targeted therapies, highlighting both approved agents and emerging therapeutic strategies. Clinical evidence supports the rational integration of PI3K inhibitors with endocrine therapy, CDK4/6 inhibitors, MAPK pathway inhibitors, dual PI3K/mTOR inhibition, and immune checkpoint blockade. In addition, accumulating evidence indicates that PIK3CA plays a pivotal role in shaping the tumor immune microenvironment, providing a biological rationale for combining PI3K inhibition with immunotherapy. Finally, we discuss future directions in precision oncology, emphasizing integrated molecular profiling, liquid biopsy, single-cell and spatial technologies, functional genomics, and evolutionary approaches as complementary strategies to refine patient selection, overcome therapeutic resistance, and optimize clinical outcomes.
Rational combination strategies are outlined that simultaneously target the RAS/MAPK axis and key TME vulnerabilities, such as immunotherapy combinations, CAF reprogramming, and ECM normalization, to overcome stromal-mediated resistance and achieve deeper, more sustained clinical responses.
Wen-Hao Ma, Xing-Yu Guo, Xiu-Ting Liu· Cancer Advances· 0 citations
Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer accounts for approximately 70% of breast cancer cases. Despite recent advances with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), resistance inevitably develops, often driven by activation of the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway. Genetic alterations such as PIK3CA mutations (present in ~ 45% of HR+/HER2- tumors), AKT1 mutations, and PTEN loss contribute to endocrine resistance and poor outcomes. This review summarizes emerging strategies targeting this pathway to overcome resistance in advanced disease. Isoform-specific PI3K inhibitors, including alpelisib and inavolisib, have demonstrated clinically meaningful progression-free survival benefits in PIK3CA-mutated populations, with inavolisib showing improved tolerability and efficacy. In contrast, pan-PI3K inhibitors such as buparlisib have been constrained by toxicity. Targeting downstream signaling, AKT inhibitors have also shown benefit: capivasertib has demonstrated clinical efficacy leading to US Food and Drug Administration approval, while ipatasertib has yielded encouraging results, particularly in tumors harboring PIK3CA, AKT1, or PTEN alterations. Mammalian target of rapamycin inhibitors, notably everolimus, have shown efficacy irrespective of mutation status. The dual PI3K-mTOR inhibitor (gedatolisib) has also shown promising progression-free survival benefit in a PIK3CA wild-type population. Next-generation agents, including mutant-selective PI3Kα inhibitors and bi-steric mTOR complex 1 inhibitors, are under active investigation. Optimal sequencing of these agents alongside endocrine therapy and CDK4/6i options remain a critical question, as does integration of genomic testing to guide therapy. Future directions include rational combination strategies, improved biomarker-driven selection, and novel modalities such as proteolysis-targeting chimeras (PROTACs). Collectively, these advances aim to enhance durability of response, minimize toxicity, and improve survival in HR+/HER2- metastatic breast cancer.
L. Lei, M. Canning, E. Sakach et al.· Drugs· 0 citations
