Resistance Mechanisms to Targeted Therapies in and Non-small Cell Lung Cancer.

Despite initial benefit from tyrosine kinase inhibitors (TKIs), patients with advanced non-small cell lung cancer (NSCLC) harboring (ALK) and (ROS1) gene fusions ultimately progress. Here, we report on the potential resistance mechanisms in a series of patients with ALK and ROS1 NSCLC progressing on different types and/or lines of -targeted therapy. We used a combination of next-generation sequencing (NGS), multiplex mutation assay, direct DNA sequencing, RT-PCR, and FISH to identify fusion variants/partners and copy-number gain (CNG), kinase domain mutations (KDM), and copy-number variations (CNVs) in other cancer-related genes. We performed testing on 12 and 43 patients. One of 12 ROS1 (8%) and 15 of 43 (35%) ALK patients harbored KDM. In the ROS1 cohort, we identified and β-catenin mutations and HER2-mediated bypass signaling as non-ROS1-dominant resistance mechanisms. In the ALK cohort, we identified a novel gene fusion, a fusion, 2 , and 3 mutations, as well as mutations in , and In addition, we identified CNV in multiple proto-oncogenes genes including and others. We identified a putative TKI resistance mechanism in six of 12 (50%) ROS1 patients and 37 of 43 (86%) ALK patients. Our data suggest that a focus on KDMs will miss most resistance mechanisms; broader gene testing strategies and functional validation is warranted to devise new therapeutic strategies for drug resistance. .