Resistance mechanisms to targeted therapies in ROS1+ and ALK+ non-small cell lung cancer

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d8864064e250">Purpose</h5> <p id="P1">Despite initial benefit from tyrosine kinase inhibitors (TKI), advanced non-small cell lung cancer (NSCLC) patients 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 ALK+ and ROS1+ NSCLC patients progressing on different types and/or lines of <i>ROS1/ALK</i> targeted therapy. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d8864064e264">Experimental Design</h5> <p id="P2">We used a combination of next generation sequencing (NGS), multiplex mutation assay, direct DNA sequencing, RT-PCR, and fluorescence <i>in situ</i> hybridization (FISH) to identify fusion variants/partners and copy number gain (CNG), kinase domain mutations (KDMs) and copy number variations (CNV) in other cancer-related genes. We performed testing on 12 <i>ROS1+</i> and 43 <i>ALK+</i> patients. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d8864064e278">Results</h5> <p id="P3">One of 12 ROS1+ (8%) and 15/43 (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>. Additionally, we identified CNV in multiple proto-oncogenes genes including <i>PDGFRA</i>, <i>KIT, KDR, GNAS, K/HRAS, RET, NTRK1, MAP2K1,</i> and others. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d8864064e314">Conclusions</h5> <p id="P4">We identified a putative TKI resistance mechanism in 6 of 12 (50%) ROS1+ patients and 37/43 (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. </p> </div>