Potential Therapeutic Strategy for EGFR-Mutant Lung Cancer With Concomitant EML4-ALK Rearrangement-Combination of EGFR Tyrosine Kinase Inhibitors and ALK Inhibitors

Ming-Hung Huang; Jih-Hsiang Lee; Pei-Shan Hung; James Chih-Hsin Yang

doi:10.1016/j.jtocrr.2022.100405

Potential Therapeutic Strategy for EGFR-Mutant Lung Cancer With Concomitant EML4-ALK Rearrangement-Combination of EGFR Tyrosine Kinase Inhibitors and ALK Inhibitors

JTO Clin Res Rep. 2022 Sep 9;3(11):100405. doi: 10.1016/j.jtocrr.2022.100405. eCollection 2022 Nov.

Authors

Ming-Hung Huang¹, Jih-Hsiang Lee^{1

2}, Pei-Shan Hung¹, James Chih-Hsin Yang^{1

2}

Affiliations

¹ Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Abstract

Introduction: Although driver gene mutations have been believed to be mutually exclusive, some patients with NSCLC and concomitant EGFR mutations and EML4-ALK rearrangements have been reported. In this study, we reported a case of a patient with lung cancer who harbored both EGFR mutation and the EML4-ALK rearrangement after acquiring resistance to the EGFR tyrosine kinase inhibitor treatment. EGFR-mutant and ALK fusion proteins were detected in the same tumor cells through immunohistochemical analysis. Investigation of the molecular mechanisms of concomitant EGFR mutation and the EML4-ALK rearrangement in the same tumor cell can help discover an appropriate treatment for these patients.

Methods: PC-9 cells, expressing EGFR exon 19 deletion, were transfected with EML4-ALK variant 3a (v3a) and variant 3b (v3b) separately and selected, and the effect of EGFR and ALK inhibitors was evaluated in vitro and in vivo.

Results: PC-9_v3a-gef and PC-9_v3b-gef cells were resistant to gefitinib and ALK inhibitors alone, but ALK inhibitors enhanced gefitinib-induced cytotoxicity. In animal studies, gefitinib completely inhibited the tumor growth in PC-9_vector cells but not in PC-9_v3a-gef and PC-9_v3b-gef cells. A combination of ALK inhibitor and gefitinib was found to be more potent than gefitinib alone in PC-9_v3a-gef and PC-9_v3b-gef cells. Furthermore, combination treatment with osimertinib and ceritinib caused a decrease in liver tumor size of the patient with liver metastases.

Conclusions: Our data suggest that combination treatment with EGFR and ALK inhibitors can be a therapeutic strategy for treating NSCLC with concomitant EGFR mutation and EML4-ALK rearrangement.

Keywords: ALK inhibitor; EGFR; EGFR-TKI; EML4-ALK; Lung cancer.