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Ref Type Journal Article
PMID (25317746)
Authors Vita M, Tisserand JC, Chauvot de Beauchêne I, Panel N, Tchertanov L, Agopian J, Mescam-Mancini L, Fouet B, Fournier B, Dubreuil P, Bertucci F, De Sepulveda P
Title Characterization of S628N: a novel KIT mutation found in a metastatic melanoma.
Journal Vol Issue Date Pages Journal Short Title
JAMA dermatology 150 12 2014 Dec 1345-9 JAMA Dermatol
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
KIT S628N KIT Inhibitor
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
KIT S628N missense gain of function KIT S628N lies within the protein kinase domain (exon 13) of the Kit protein (UniProt.org). S628N results in constitutive Kit phosphorylation and activation of downstream Stat3, Akt and Erk1/2, and is transforming in cell culture (PMID: 25317746).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References