Data from Identifying and Targeting <i>ROS1</i> Gene Fusions in Non–Small Cell Lung Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> Oncogenic gene fusions involving the 3′ region of <i>ROS1</i> kinase have been identified in various human cancers. In this study, we sought to characterize <i>ROS1</i> fusion genes in non–small cell lung cancer (NSCLC) and establish the fusion proteins as drug targets.</p><p><b>Experimental Design:</b> An NSCLC tissue microarray (TMA) panel containing 447 samples was screened for <i>ROS1</i> rearrangement by FISH. This assay was also used to screen patients with NSCLC. In positive samples, the identity of the fusion partner was determined through inverse PCR and reverse transcriptase PCR. In addition, the clinical efficacy of ROS1 inhibition was assessed by treating a ROS1-positive patient with crizotinib. The HCC78 cell line, which expresses the <i>SLC34A2–ROS1</i> fusion, was treated with kinase inhibitors that have activity against ROS1. The effects of ROS1 inhibition on proliferation, cell-cycle progression, and cell signaling pathways were analyzed by MTS assay, flow cytometry, and Western blotting.</p><p><b>Results:</b> In the TMA panel, 5 of 428 (1.2%) evaluable samples were found to be positive for <i>ROS1</i> rearrangement. In addition, 1 of 48 patients tested positive for rearrangement, and this patient showed tumor shrinkage upon treatment with crizotinib. The patient and one TMA sample displayed expression of the recently identified <i>SDC4–ROS1</i> fusion, whereas two TMA samples expressed the <i>CD74–ROS1</i> fusion and two others expressed the <i>SLC34A2–ROS1</i> fusion. In HCC78 cells, treatment with ROS1 inhibitors was antiproliferative and downregulated signaling pathways that are critical for growth and survival.</p><p><b>Conclusions:</b> ROS1 inhibition may be an effective treatment strategy for the subset of patients with NSCLC whose tumors express <i>ROS1</i> fusion genes. <i>Clin Cancer Res; 18(17); 4570–9. ©2012 AACR</i>.</p></div>