Research Progress on Resistance Mechanisms and Post-Resistance Treatment of Targeted Therapy in Non-Small Cell Lung Cancer

Ziyuan Gao; Yuzhu Chen

doi:10.54097/8kv89j18

Authors

Ziyuan Gao
Yuzhu Chen

DOI:

https://doi.org/10.54097/8kv89j18

Keywords:

Non-small Cell Lung Cancer (NSCLC), Targeted Therapy, EGFR-TKIs, Acquired Resistance

Abstract

Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related mortality worldwide, and about 60% of the advanced cancer stage patients carry particular molecular mutations that model potential targets in terms of targeted therapy. Gene mutations such as EGFR, MET, and ALK are key drivers of NSCLC. Targeted drugs against these mutations, including EGFR-TKIs, MET-TKIs, and ALK-TKIs, have significantly improved patient prognosis. However, acquired resistance remains a significant challenge, with mechanisms involving secondary target mutations, bypass activation, and phenotypic transformation. This review summarizes the resistance mechanisms of targeted therapy in NSCLC and corresponding therapeutic strategies, aiming to provide new insights for post-resistance treatment.

Downloads

Download data is not yet available.

References

[1] Bray, F., et al., Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018. 68(6): p. 394-424.

[2] Alduais, Y., et al., Non-small cell lung cancer (NSCLC): A review of risk factors, diagnosis, and treatment. Medicine (Baltimore), 2023. 102(8): p. e32899.

[3] Wu, L., et al., Development of EGFR TKIs and Options to Manage Resistance of Third-Generation EGFR TKI Osimertinib: Conventional Ways and Immune Checkpoint Inhibitors. Front Oncol, 2020. 10: p. 602762.

[4] Michaels, E. and C.M. Bestvina, Meeting an un-MET need: Targeting MET in non-small cell lung cancer. Front Oncol, 2022. 12: p. 1004198.

[5] Herbst, R.S., D. Morgensztern, and C. Boshoff, The biology and management of non-small cell lung cancer. Nature, 2018. 553(7689): p. 446-454.

[6] Yun, C.H., et al., The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A, 2008. 105(6): p. 2070-5.

[7] Patel, H., et al., Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance. Eur J Med Chem, 2017. 142: p. 32-47.

[8] Yu, H.A., et al., Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res, 2013. 19(8): p. 2240-7.

[9] Engelman, J.A., et al., MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science, 2007. 316(5827): p. 1039-43.

[10] Bean, J., et al., MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A, 2007. 104(52): p. 20932-7.

[11] Lee, J.K., et al., Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas. J Clin Oncol, 2017. 35(26): p. 3065-3074.

[12] Recondo, G., et al., Molecular Mechanisms of Acquired Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14-Mutant NSCLC. Clin Cancer Res, 2020. 26(11): p. 2615-2625.

[13] Guo, R., et al., MET Exon 14-altered Lung Cancers and MET Inhibitor Resistance. Clin Cancer Res, 2021. 27(3): p. 799-806.

[14] Solomon, B.J., et al., Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study. J Clin Oncol, 2024. 42(29): p. 3400-3409.

[15] ClinicalTrials.gov. A Study of BDTX-1535 in Patients With Glioblastoma or Non-Small Cell Lung Cancer. 2022 2025-3-25]; Available from: https://clinicaltrials.gov/study/NCT05256290.

[16] Yu, H.A., et al., Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD). Clin Lung Cancer, 2021. 22(6): p. 601-606.

[17] Wu, Y.L., et al., Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial. Lancet Oncol, 2024. 25(8): p. 989-1002.

[18] Goto, K., et al., Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. J Clin Oncol, 2023. 41(31): p. 4852-4863.

[19] Planchard, D., et al., Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol, 2016. 17(5): p. 642-50.

[20] Planchard, D., et al., Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol, 2017. 18(10): p. 1307-1316.

[21] Yu, H.A., et al., HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy. J Clin Oncol, 2023. 41(35): p. 5363-5375.

[22] Lee, S.H., et al., MA13.06 Amivantamab, Lazertinib Plus Platinum-based Chemotherapy in EGFR-mutated Advanced NSCLC: Updated Results from CHRYSALIS-2. Journal of Thoracic Oncology, 2023. 18(11): p. S146-S147.

[23] Hartmaier, R.J., et al., Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Non-Small Cell Lung Cancer: TATTON. Cancer Discov, 2023. 13(1): p. 98-113.

[24] Nogami, N., et al., IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain. J Thorac Oncol, 2022. 17(2): p. 309-323.

[25] Lu, S., et al., Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med, 2023. 11(7): p. 624-636.

[26] Soria, J.C., et al., Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med, 2018. 378(2): p. 113-125.

[27] Odogwu, L., et al., FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring BRAF V600E Mutations. Oncologist, 2018. 23(6): p. 740-745.

[28] Ahn, M.J., et al., Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study. J Clin Oncol, 2025. 43(3): p. 260-272.

[29] Fujino, T., et al., Foretinib can overcome common on-target resistance mutations after capmatinib/ tepotinib treatment in NSCLCs with MET exon 14 skipping mutation. J Hematol Oncol, 2022. 15(1): p. 79.

[30] Kato, T., et al., Efficacy and safety of tepotinib in Asian patients with advanced NSCLC with MET exon 14 skipping enrolled in VISION. Br J Cancer, 2024. 130(10): p. 1679-1686.

[31] Jamme, P., et al., Alterations in the PI3K Pathway Drive Resistance to MET Inhibitors in NSCLC Harboring MET Exon 14 Skipping Mutations. J Thorac Oncol, 2020. 15(5): p. 741-751.

[32] Shiba-Ishii, A., et al., Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer. Nat Cancer, 2022. 3(6): p. 710-722.

[33] Shaw, A.T., et al., ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer. J Clin Oncol, 2019. 37(16): p. 1370-1379.

[34] Gainor, J.F., et al., Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov, 2016. 6(10): p. 1118-1133.

[35] Dagogo-Jack, I., et al., Treatment with Next-Generation ALK Inhibitors Fuels Plasma ALK Mutation Diversity. Clin Cancer Res, 2019. 25(22): p. 6662-6670.

[36] Yoda, S., et al., Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer. Cancer Discov, 2018. 8(6): p. 714-729.

[37] Crystal, A.S., et al., Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science, 2014. 346(6216): p. 1480-6.

[38] Hrustanovic, G., et al., RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nat Med, 2015. 21(9): p. 1038-47.

[39] Kim, D.W., et al., Brigatinib in Patients with Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial. J Clin Oncol, 2017. 35 (22): p. 2490-2498.

[40] Felip, E., et al., Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs. Ann Oncol, 2021. 32(5): p. 620-630.

[41] Wolf, J., et al., Capmatinib in MET exon 14-mutated non-small-cell lung cancer: final results from the open-label, phase 2 GEOMETRY mono-1 trial. Lancet Oncol, 2024. 25(10): p. 1357-1370.

[42] Sadida, H.Q., et al., Epigenetic modifications: Key players in cancer heterogeneity and drug resistance. Transl Oncol, 2024. 39: p. 101821.