title: Identification of Targetable Kinase Alterations in Patients with Colorectal Carcinoma That are Preferentially Associated with Wild-Type RAS/RAF.
abstract: 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 MAP2K1 (MEK1) 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 MAP2K1. 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 MAP2K1 hotspot mutations (n = 7), respectively. RTK-altered cases had fewer concurrent RAS/RAF mutations (P = 0.003) than RTK/MAP2K1 wild-type colorectal carcinoma. MAP2K1-mutated colorectal carcinoma 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, and ETV6-NTRK3. Only 1 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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. hechtmaj@mskcc.org.
authors.forename: Jaclyn F
authors.initials: JF
authors.lastname: Hechtman
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Zehir
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Rona
authors.initials: R
authors.lastname: Yaeger
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sumit
authors.initials: S
authors.lastname: Middha
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Tao
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David M
authors.initials: DM
authors.lastname: Hyman
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Solit
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Borsu
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Leonard
authors.initials: L
authors.lastname: Saltz
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
mesh_terms: D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D048490:raf Kinases / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D020794:Receptor Protein-Tyrosine Kinases; D048490:raf Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D018631:ras Proteins