Targeted Therapy and Drug Resistance of EGFR Mutations in Non-Small Cell Lung Cancer

Yihui Liao

doi:10.54097/w9853r45

Authors

Yihui Liao

DOI:

https://doi.org/10.54097/w9853r45

Keywords:

Tyrosine kinase inhibitors, EGFR, T790M, C797S, NSCLC.

Abstract

Lung cancer remains one of the most lethal malignancies, with non-small cell lung cancer (NSCLS) being the predominant subtype. Activating mutations in the epidermal growth factor receptor (EGFR) increase the receptor's affinity for ATP, leading to sustained downstream signaling and uninhibited tumor proliferation. Small-molecule EGFR inhibitors have transformed treatment, with Osimertinib significantly prolonging progression-free and overall survival while improving control of brain metastases. Long-term treatment inevitably leads to drug resistance, often through targeted secondary or tertiary EGFR mutations (e.g., T790M and C797S), activation of bypass pathways involving MET, HER2, and FGFR, and histologic or phenotypic transformation. These challenges highlight the need for personalized treatment strategies guided by molecular profiling and active monitoring. In recent years, treatment strategies have expanded to include fourth-generation EGFR allosteric inhibitors, antibody-drug conjugates, rational combinations targeting alternative signaling pathways, and immunotherapy. This review will summarize the current evidence for EGFR-targeted therapies, highlight established and emerging mechanisms of resistance, and discuss emerging approaches that may help optimize clinical outcomes.

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References

[1] Wang R., Luo Z., Zhang H., et al. Tanshinone IIA reverses gefitinib-resistance in human non-small-cell lung cancer via regulation of VEGFR/Akt pathway. OncoTargets and Therapy, 2019, 12: 9355 - 9365.

[2] Wu L., Ke L., Zhang Z., et al. Development of EGFR TKIs and options to manage resistance of third-generation EGFR TKI Osimertinib: conventional ways and immune checkpoint inhibitors. Frontiers in Oncology, 2020, 10: 602762.

[3] Kitadai R., Okuma Y. Treatment strategies for non-small cell lung cancer harboring common and uncommon EGFR mutations: drug sensitivity based on exon classification, and structure-function analysis. Cancers, 2022, 14 (10): 2519.

[4] Yang J.C.H., Sequist L.V., Geater S.L., et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. The Lancet Oncology, 2015, 16 (7): 830 - 838.

[5] Ponnusamy M.P., Singh A.P., Jain M., et al. MUC4 activates HER2 signalling and enhances the motility of human ovarian cancer cells. British Journal of Cancer, 2008, 99 (3): 520 - 526.

[6] Lin D.C., Xu L., Chen Y., et al. Genomic and functional analysis of the E3 ligase PARK2 in glioma. Cancer Research, 2015, 75 (9): 1815 - 1827.

[7] Halder S., Basu S., Lall S.P., et al. Targeting the EGFR signaling pathway in cancer therapy: what’s new in 2023? Expert Opinion on Therapeutic Targets, 2023, 27 (4 - 5): 305 - 324.

[8] Bhatia R., Siddiqui J.A., Ganguly K., et al. Muc4 loss mitigates epidermal growth factor receptor activity essential for PDAC tumorigenesis. Oncogene, 2023, 42 (10): 759 - 770.

[9] Chaturvedi P., Singh A.P., Chakraborty S., et al. MUC4 mucin interacts with and stabilizes the HER2 oncoprotein in human pancreatic cancer cells. Cancer Research, 2008, 68 (7): 2065 - 2070.

[10] Papadimitrakopoulou V.A., Wu Y.L., Han J.Y., et al. Analysis of resistance mechanisms to Osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. Annals of Oncology, 2018, 29: 486 - 495.

[11] Cho J.H., Lim S.H., An H.J., et al. Osimertinib for patients with non-small-cell lung cancer harboring uncommon EGFR mutations: a multicenter, open-label, phase II trial (KCSG-LU15-09). Journal of Clinical Oncology, 2020, 38 (5): 488 - 495.

[12] Oxnard G.R., Hu Y.B., Mileham K.F., et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib. JAMA Oncology, 2018, 4 (11): 1527 - 1534.

[13] Xu H.Q., Zhang H.J., Jia S.Y., et al. Diethenyl sulfoximine (DESI) as an irreversible lysine-targeting warhead enables the design of covalent allosteric EGFR inhibitor. Chemistry–A European Journal, 2025, 31 (41): e202500009.

[14] Eno M.S., Brubaker J.D., Campbell J.E., et al. Discovery of BLU-945, a reversible, potent, and wild-type-sparing next-generation EGFR mutant inhibitor for treatment-resistant non-small-cell lung cancer. Journal of Medicinal Chemistry, 2022, 65 (14): 9662 - 9677.

[15] Passaro A., Wang J., Wang Y., et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on Osimertinib: primary results from the phase III MARIPOSA-2 study. Annals of Oncology, 2024, 35 (1): 77 - 90.

[16] Hartmaier R.J., Markovets A.A., Ahn M.J., et al. Osimertinib plus savolitinib to overcome acquired MET-mediated resistance in epidermal growth factor receptor-mutated, MET-amplified non-small cell lung cancer: TATTON. Cancer Discovery, 2023, 13 (1): 98 - 113.