Potential Utility of a 4th-Generation EGFR-TKI and Exploration of Resistance Mechanisms-An In Vitro Study

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2024 Jul 27

PMID 39061985

Authors

Shota Fukuda

Kenichi Suda

Akira Hamada

Hana Oiki

Shuta Ohara

Masaoki Ito

Junichi Soh

Tetsuya Mitsudomi

Yasuhiro Tsutani

Affiliations

Soon will be listed here.

Abstract

The emergence of acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) is almost inevitable even after a remarkable clinical response. Secondary mutations such as T790M and C797S are responsible for the resistance to 1st/2nd-generation (1/2G) TKIs and 3G TKIs, respectively. To overcome both the T790M and C797S mutations, novel 4G EGFR-TKIs are now under early clinical development. In this study, we evaluated the efficacy of a 4G EGFR-TKI in the treatment of lung cancer with mutation as well as explored resistance mechanisms to a 4G TKI. First, we compared the efficacies of seven TKIs including a 4G TKI, BI4020, against Ba/F3 cell models that simulate resistant tumors after front-line osimertinib treatment failure because of a secondary mutation. We also established acquired resistant cells to BI4020 by chronic drug exposure. Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib). BI4020 inhibited the growth of C797S-positive cells; however, it was not effective against L718Q-positive cells. Erlotinib was active against all Ba/F3 cells tested. In the analysis of resistance mechanisms of BI4020-resistant (BIR) cells, none harbored secondary mutations. HCC827BIR cells had gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020. HCC4006BIR and H1975BIR cells exhibited epithelial-to-mesenchymal transition. This study suggests that erlotinib may be more suitable than 4G TKIs to overcome secondary mutations after front-line osimertinib. We found that off-target mechanisms that cause resistance to earlier-generation TKIs will also cause resistance to 4G TKIs.

Citing Articles

Optimizing Osimertinib for NSCLC: Targeting Resistance and Exploring Combination Therapeutics.

Liao Y, Tsai C, Huang H Cancers (Basel). 2025; 17(3).

PMID: 39941826 PMC: 11815769. DOI: 10.3390/cancers17030459.

References

Uchibori K, Inase N, Nishio M, Fujita N, Katayama R . Identification of Mutation Accumulation as Resistance Mechanism Emerging in First-Line Osimertinib Treatment. J Thorac Oncol. 2018; 13(7):915-925. DOI: 10.1016/j.jtho.2018.04.005. View

Schmid S, Li J, Leighl N . Mechanisms of osimertinib resistance and emerging treatment options. Lung Cancer. 2020; 147:123-129. DOI: 10.1016/j.lungcan.2020.07.014. View

Fassunke J, Muller F, Keul M, Michels S, Dammert M, Schmitt A . Overcoming EGFR-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors. Nat Commun. 2018; 9(1):4655. PMC: 6220297. DOI: 10.1038/s41467-018-07078-0. View

Kim Y, Ko J, Cui Z, Abolhoda A, Ahn J, Ou S . The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor. Mol Cancer Ther. 2012; 11(3):784-91. DOI: 10.1158/1535-7163.MCT-11-0750. View

Ramalingam S, Vansteenkiste J, Planchard D, Cho B, Gray J, Ohe Y . Overall Survival with Osimertinib in Untreated, -Mutated Advanced NSCLC. N Engl J Med. 2019; 382(1):41-50. DOI: 10.1056/NEJMoa1913662. View

Koga T, Suda K, Nishino M, Fujino T, Ohara S, Hamada A . Activity and mechanism of acquired resistance to tarloxotinib in mutant lung cancer: an study. Transl Lung Cancer Res. 2021; 10(8):3659-3670. PMC: 8435395. DOI: 10.21037/tlcr-21-216. View

Cappuzzo F, Janne P, Skokan M, Finocchiaro G, Rossi E, Ligorio C . MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Ann Oncol. 2008; 20(2):298-304. PMC: 2733067. DOI: 10.1093/annonc/mdn635. View

Schoenfeld A, Chan J, Kubota D, Sato H, Rizvi H, Daneshbod Y . Tumor Analyses Reveal Squamous Transformation and Off-Target Alterations As Early Resistance Mechanisms to First-line Osimertinib in -Mutant Lung Cancer. Clin Cancer Res. 2020; 26(11):2654-2663. PMC: 7448565. DOI: 10.1158/1078-0432.CCR-19-3563. View

Suda K, Mizuuchi H, Maehara Y, Mitsudomi T . Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny. Cancer Metastasis Rev. 2012; 31(3-4):807-14. DOI: 10.1007/s10555-012-9391-7. View

10.

Suda K, Murakami I, Obata K, Sakai K, Fujino T, Koga T . Spatial heterogeneity of acquired resistance mechanisms to 1st/2nd generation EGFR tyrosine kinase inhibitors in lung cancer. Lung Cancer. 2020; 148:100-104. DOI: 10.1016/j.lungcan.2020.08.010. View

11.

Uozu S, Imaizumi K, Yamaguchi T, Goto Y, Kawada K, Minezawa T . Feasibility of tissue re-biopsy in non-small cell lung cancers resistant to previous epidermal growth factor receptor tyrosine kinase inhibitor therapies. BMC Pulm Med. 2017; 17(1):175. PMC: 5719748. DOI: 10.1186/s12890-017-0514-3. View

12.

Nishino M, Suda K, Kobayashi Y, Ohara S, Fujino T, Koga T . Effects of secondary EGFR mutations on resistance against upfront osimertinib in cells with EGFR-activating mutations in vitro. Lung Cancer. 2018; 126:149-155. DOI: 10.1016/j.lungcan.2018.10.026. View

13.

Yoshida T, Song L, Bai Y, Kinose F, Li J, Ohaegbulam K . ZEB1 Mediates Acquired Resistance to the Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. PLoS One. 2016; 11(1):e0147344. PMC: 4720447. DOI: 10.1371/journal.pone.0147344. View

14.

Planchard D, Janne P, Cheng Y, Yang J, Yanagitani N, Kim S . Osimertinib with or without Chemotherapy in -Mutated Advanced NSCLC. N Engl J Med. 2023; 389(21):1935-1948. DOI: 10.1056/NEJMoa2306434. View

15.

Rangachari D, To C, Shpilsky J, VanderLaan P, Kobayashi S, Mushajiang M . EGFR-Mutated Lung Cancers Resistant to Osimertinib through EGFR C797S Respond to First-Generation Reversible EGFR Inhibitors but Eventually Acquire EGFR T790M/C797S in Preclinical Models and Clinical Samples. J Thorac Oncol. 2019; 14(11):1995-2002. PMC: 6823139. DOI: 10.1016/j.jtho.2019.07.016. View

16.

Ercan D, Choi H, Yun C, Capelletti M, Xie T, Eck M . EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors. Clin Cancer Res. 2015; 21(17):3913-23. PMC: 4791951. DOI: 10.1158/1078-0432.CCR-14-2789. View

17.

Wu Y, Cheng Y, Zhou J, Lu S, Zhang Y, Zhao J . Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial. Lancet Respir Med. 2020; 8(11):1132-1143. DOI: 10.1016/S2213-2600(20)30154-5. View

18.

Yu H, Tian S, Drilon A, Borsu L, Riely G, Arcila M . Acquired Resistance of EGFR-Mutant Lung Cancer to a T790M-Specific EGFR Inhibitor: Emergence of a Third Mutation (C797S) in the EGFR Tyrosine Kinase Domain. JAMA Oncol. 2015; 1(7):982-4. PMC: 4665629. DOI: 10.1001/jamaoncol.2015.1066. View

19.

Chen J, Facchinetti F, Braye F, Yurchenko A, Bigot L, Ponce S . Single-cell DNA-seq depicts clonal evolution of multiple driver alterations in osimertinib-resistant patients. Ann Oncol. 2022; 33(4):434-444. DOI: 10.1016/j.annonc.2022.01.004. View

20.

Sakata Y, Sakata S, Oya Y, Tamiya M, Suzuki H, Shibaki R . Osimertinib as first-line treatment for advanced epidermal growth factor receptor mutation-positive non-small-cell lung cancer in a real-world setting (OSI-FACT). Eur J Cancer. 2021; 159:144-153. DOI: 10.1016/j.ejca.2021.09.041. View