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

Jaclyn F Hechtman, Ahmet Zehir, Rona Yaeger, Lu Wang, Sumit Middha, Tao Zheng, David M Hyman, David Solit, Maria E Arcila, Laetitia Borsu, Jinru Shia, Efsevia Vakiani, Leonard Saltz, Marc Ladanyi

Targeted therapy for metastatic colorectal carcinoma (CRC) 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 MAP2K1 (MEK1) mutations in a large cohort of CRC patients studied by MSK-IMPACT and TCGA, focusing on amplifications, fusions, and hotspot mutations in RTK genes and MAP2K1. RTK gene amplifications were confirmed with fluorescence in situ hybridization (FISH) and immunohistochemical (IHC) staining. Among 751 CRC cases with next-gen sequencing (NGS) data, 7% and 1% of CRC harbored RTK alterations and MAP2K1 hotspot mutations (n=7), respectively. RTK altered cases had fewer concurrent RAS/ RAF mutation (p=0.003) than RTK/ MAP2K1 wild type CRC. MAP2K1-mutated CRC showed no RAS/RAF mutations. ERBB2 (n = 32) and EGFR (n=13) were the most frequently altered RTKs, both activated by amplification and/or hotspot mutations. Three RTK fusions were identified: NCOA4-RET, ERBB2-GRB7, ETV6-NTRK3. Only one of 6 patients with an RTK or MAP2K1 alteration who received anti-EGFR and/ or anti-ERBB2 therapy demonstrated stable disease; the rest progressed immediately. Overall, RTK alterations and MAP2K1 mutations occur in approximately 8% of CRC. 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 CRC and as negative predictors of response to anti-EGFR therapy. 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.