Resistance Mechanisms to Targeted Therapies in <i>ROS1</i> + and <i>ALK</i> + Non–small Cell Lung Cancer

Abstract

<b>Purpose:</b> Despite initial benefit from tyrosine kinase inhibitors (TKIs), patients with advanced non-small cell lung cancer (NSCLC) harboring <i>ALK</i> (ALK⁺) and <i>ROS1</i> (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 <i>ROS1/ALK</i>-targeted therapy.<b>Experimental Design:</b> 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 <i>ROS1⁺</i> and 43 <i>ALK⁺</i> patients.<b>Results:</b> One of 12 ROS1⁺ (8%) and 15 of 43 (35%) ALK <i>⁺</i> patients harbored KDM. In the ROS1⁺ cohort, we identified <i>KIT</i> and β-catenin mutations and HER2-mediated bypass signaling as non-ROS1-dominant resistance mechanisms. In the ALK⁺ cohort, we identified a novel <i>NRG1</i> gene fusion, a <i>RET</i> fusion, 2 <i>EGFR</i>, and 3 <i>KRAS</i> mutations, as well as mutations in <i>IDH1, RIT1, NOTCH</i>, and <i>NF1</i> In addition, we identified CNV in multiple proto-oncogenes genes including <i>PDGFRA, KIT, KDR, GNAS, K/HRAS, RET, NTRK1, MAP2K1,</i> and others.<b>Conclusions:</b> We identified a putative TKI resistance mechanism in six of 12 (50%) ROS1 <i>⁺</i> 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. <i>Clin Cancer Res; 24(14); 3334-47. ©2018 AACR</i>.