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Ref Type Journal Article
PMID (15790786)
Authors Growney JD, Clark JJ, Adelsperger J, Stone R, Fabbro D, Griffin JD, Gilliland DG
Title Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412.
Abstract Text Constitutively activated forms of the transmembrane receptor tyrosine kinase c-KIT have been associated with systemic mast cell disease, acute myeloid leukemia, and gastrointestinal stromal tumors. Reports of the resistance of the kinase domain mutation D816V to the adenosine triphosphate (ATP)-competitive kinase inhibitor imatinib mesylate prompted us to characterize 14 c-KIT mutations reported in association with human hematologic malignancies for transforming activity in the murine hematopoietic cell line Ba/F3 and for sensitivity to the tyrosine kinase inhibitor PKC412. Ten of 14 c-KIT mutations conferred interleukin 3 (IL-3)-independent growth. c-KIT D816Y and D816V transformed cells were sensitive to PKC412 despite resistance to imatinib mesylate. In these cells, PKC412, but not imatinib mesylate, inhibited autophosphorylation of c-KIT and activation of downstream effectors signal transducer and transcriptional activator 5 (Stat5) and Stat3. Variable sensitivities to PKC412 or imatinib mesylate were observed among other mutants. These findings suggest that PKC412 may be a useful therapeutic agent for c-KIT-positive malignancies harboring the imatinib mesylate-resistant D816V or D816Y activation mutations.


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Molecular Profile Treatment Approach
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 A502_Y503dup duplication gain of function KIT A502_Y503dup (also referred to as Y503_F504insAY) indicates the insertion of 2 duplicate amino acids, alanine (A)-502 through tyrosine (Y)-503, in the Ig-like C2-type domain 5 (exon 9) of the Kit protein ( A502_Y503dup results in constitutive phosphorylation of Kit and is transforming in cell culture (PMID: 15790786, PMID: 19865100).
KIT E839K missense loss of function KIT E839K lies within the tyrosine kinase domain 2 of the Kit protein (PMID: 17555444). E839K results in impaired Kit protein maturation, a loss of Kit phosphorylation, and dominant inhibition of activating Kit mutations in cultured cells (PMID: 9990072, PMID: 15790786).
KIT R634W missense gain of function KIT R634W lies within the protein kinase domain (exon 13) of the Kit protein ( R634W confers a gain of function to the Kit protein as demonstrated by constitutive Kit phosphorylation, increased Stat3 and Stat5 phosphorylation, and is transforming in cell culture (PMID: 15790786).
KIT W557R missense unknown KIT W557R lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 15790786). W557R has been identified in the scientific literature (PMID: 15869870, PMID: 12824871, PMID: 26848617) but has not been biochemically characterized and therefore, its effect on Kit protein funciton is unknown (PubMed, Nov 2023).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT D816V Advanced Solid Tumor resistant Imatinib Preclinical Actionable In a preclinical study, transformed cells expressing KIT D816V demonstrated resistance to Gleevec (imatinib mesylate) in culture (PMID: 15790786). 15790786