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

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

Methods: PC-9 cells, expressing exon 19 deletion, were transfected with 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 mutation and rearrangement.