title: Characterization of S628N: a novel KIT mutation found in a metastatic melanoma.
abstract: IMPORTANCE The KIT receptor is mutated in approximately 15%of acral, mucosal, and chronic, sun-damaged melanomas. The status of KIT mutations is of interest because they usually are mutually exclusive with N-RAS and B-RAF mutations and because of the availability of KIT kinase inhibitors in the clinic. Some recurrent KIT mutations are well characterized; others are poorly described.OBSERVATIONS We describe a novel KIT mutation in a patient with metastatic melanoma. The mutation, located in exon 13, resulted in S628N substitution in the KIT receptor. Using all-atom molecular dynamics simulations, biochemical assays, and cell-based assays, we showed that the mutation is a bona fide gain-of-function oncogenic mutation. Furthermore,we evaluated the sensitivity of the mutant to imatinib and dasatinib.CONCLUSIONS AND RELEVANCE We report a novel KIT gain-of-function mutation with S628N substitution (exon 13) and show that it is sensitive to imatinib in vitro. Therefore, patients with this mutation may be eligible for KIT kinase inhibitor–based therapy. Further studies are needed to evaluate the clinical benefit of such therapy.
authors.forename: Marina
authors.initials: M
authors.lastname: Vita
authors.forename: Julie C
authors.initials: JC
authors.lastname: Tisserand
authors.forename: Isaure
authors.initials: I
authors.lastname: Chauvot de Beauchêne
authors.forename: Nicolas
authors.initials: N
authors.lastname: Panel
authors.forename: Luba
authors.initials: L
authors.lastname: Tchertanov
authors.forename: Julie
authors.initials: J
authors.lastname: Agopian
authors.forename: Lenaïg
authors.initials: L
authors.lastname: Mescam-Mancini
authors.forename: Bernard
authors.initials: B
authors.lastname: Fouet
authors.forename: Béatrice
authors.initials: B
authors.lastname: Fournier
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.forename: Paulo
authors.initials: P
authors.lastname: De Sepulveda
mesh_terms: D000369:Aged, 80 and over; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D000069439:Dasatinib; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D000068877:Imatinib Mesylate; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary; D008545:Melanoma / Q000235:genetics* / Q000556:secondary; D020125:Mutation, Missense; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D017354:Point Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D013125:Spinal Neoplasms / Q000235:genetics* / Q000556:secondary; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D000069439:Dasatinib