Data from Identification of Targetable Kinase Alterations in Patients with Colorectal Carcinoma That are Preferentially Associated with Wild-Type RAS/RAF

Abstract

<div>Abstract<p>Targeted therapy for metastatic colorectal carcinoma consists of anti-EGFR therapy for patients with RAS/RAF wild-type tumors. However, the response rate remains low, suggesting the presence of alternative drivers possibly also representing potential therapeutic targets. We investigated receptor tyrosine kinase (RTK) alterations and <i>MAP2K1</i> (<i>MEK1</i>) mutations in a large cohort of colorectal carcinoma patients studied by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and The Cancer Genome Atlas, focusing on amplifications, fusions, and hotspot mutations in RTK genes and <i>MAP2K1</i>. RTK gene amplifications were confirmed with FISH and immunohistochemical (IHC) staining. Among 751 colorectal carcinoma cases with next-generation sequencing data, 7% and 1% of colorectal carcinoma harbored RTK alterations and <i>MAP2K1</i> hotspot mutations (<i>n</i> = 7), respectively. RTK-altered cases had fewer concurrent RAS/RAF mutations (<i>P</i> = 0.003) than RTK/<i>MAP2K1</i> wild-type colorectal carcinoma. <i>MAP2K1</i>-mutated colorectal carcinoma showed no RAS/RAF mutations. <i>ERBB2</i> (<i>n</i> = 32) and <i>EGFR</i> (<i>n</i> = 13) were the most frequently altered RTKs, both activated by amplification and/or hotspot mutations. Three RTK fusions were identified: <i>NCOA4</i>-<i>RET</i>, <i>ERBB2</i>-<i>GRB7</i>, and <i>ETV6</i>-<i>NTRK3</i>. Only 1 of 6 patients with an RTK or <i>MAP2K1</i> alteration who received anti-EGFR and/or anti-ERBB2 therapy demonstrated stable disease; the rest progressed immediately. Overall, RTK alterations and <i>MAP2K1</i> mutations occur in approximately 8% of colorectal carcinoma. In spite of the usual absence of RAS/RAF mutations, response to anti-EGFR and/or anti-ERBB2 therapy was poor in this limited group. Larger studies are warranted to further define these kinase alterations as novel therapeutic targets in colorectal carcinoma and as negative predictors of response to anti-EGFR therapy.</p><p><b>Implications:</b> Targetable kinase alterations were identified in a subset of advanced colorectal carcinoma patients, preferentially associated with wild-type RAS/RAF, and may predict poor response to standard anti-EGFR therapy. <i>Mol Cancer Res; 14(3); 296–301. ©2015 AACR</i>.</p></div>