Other Driver Genes as Resistance Mechanisms of ALK Inhibitors in ALK-Rearranged Lung Adenocarcinoma

Author(s): Xiao-Cheng Lin, Qian-Yu Wang, Xu-Hui Guan, Yu-Fa Li, Hai-Yan Tu, Hua-Jun Chen, Jin-Ji Yang

Introduction: Other dependent driver genes, including MET, EGFR and BRAF, can cause resistance to the first- and second-generation ALK inhibitors. In vitro studies have shown that individualized intervention against these resistance pathways may be an optional treatment. We aimed to explore the clinical characteristics of patients with other dependent driver genes as resistance mechanisms to ALK inhibitors.

Methods: We performed next-generation sequencing on tissue and liquid samples obtained at every treatment milestone from three ALK-rearranged patients with advanced lung adenocarcinoma receiving targeted therapy. FISH and IHC were underwent in some tissue samples to verify the existence of ALK rearrangement and MET amplification

Results: Three patients revealed other driver gene alteration after resistance to the first- and second-generation ALK inhibitors (one BRAF V600E mutation, one EGFR L858R mutation and one MET amplification). Combination targeted therapy could overcome the resistance of acquired other driver gene alteration. When BRAF V600E, EGFR mutations and MET amplification occurred as resistance mechanisms of ALK inhibitors, they performed gene heterogeneity. Pleural effusion only revealed BRAF V600E mutation in Patient 1 and EGFR L858R mutation only showed up in cerebrospinal fluid and peripheral blood by NGS in Patient 2. MET amplification individually occurred in adrenal gland in Patient 3.

Conclusions: BRAF V600E, EGFR mutations and MET amplification could be served as resistance mechanisms of targeted therapy in ALK-rearranged lung adenocarcinoma. Dabrafenib and trametinib might overcome such resistance in acquired BRAF V600E-mutant patients. Other driver genes as resistance mechanisms of ALK inhibitors may have heterogeneity.