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|Ref Type||Journal Article|
|Authors||Gajiwala KS, Wu JC, Christensen J, Deshmukh GD, Diehl W, DiNitto JP, English JM, Greig MJ, He YA, Jacques SL, Lunney EA, McTigue M, Molina D, Quenzer T, Wells PA, Yu X, Zhang Y, Zou A, Emmett MR, Marshall AG, Zhang HM, Demetri GD|
|Title||KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients.|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Date||2009 Feb 3|
|Abstract Text||Most gastrointestinal stromal tumors (GISTs) exhibit aberrant activation of the receptor tyrosine kinase (RTK) KIT. The efficacy of the inhibitors imatinib mesylate and sunitinib malate in GIST patients has been linked to their inhibition of these mutant KIT proteins. However, patients on imatinib can acquire secondary KIT mutations that render the protein insensitive to the inhibitor. Sunitinib has shown efficacy against certain imatinib-resistant mutants, although a subset that resides in the activation loop, including D816H/V, remains resistant. Biochemical and structural studies were undertaken to determine the molecular basis of sunitinib resistance. Our results show that sunitinib targets the autoinhibited conformation of WT KIT and that the D816H mutant undergoes a shift in conformational equilibrium toward the active state. These findings provide a structural and enzymologic explanation for the resistance profile observed with the KIT inhibitors. Prospectively, they have implications for understanding oncogenic kinase mutants and for circumventing drug resistance.|
|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||D816H||missense||gain of function||KIT D816H lies within the tyrosine kinase domain region 2 (exon 17) of the Kit protein (PMID: 19164557). D816H results in increased kinase activity, constitutive Kit phosphorylation, activation of Stat3 signaling, and transformation of cultured cells (PMID: 10362788, PMID: 11494148), and confers resistance to some Kit inhibitors (PMID: 25239608).||Y|
|KIT||D816V||missense||gain of function||KIT D816V lies within the tyrosine kinase domain 2 of the Kit protein (PMID: 19865100). D816V results in constitutive phosphorylation of Kit, activation of Stat5 signaling (PMID: 19865100, PMID: 18390729), induces mastocytosis and tumor formation in mice (PMID: 21148330) and confers resistance to Kit inhibitors (PMID: 22301675, PMID: 19164557).||Y|
|KIT||V560D||missense||gain of function||KIT V560D lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 19164557). V560D confers a gain of function to Kit, as indicated by constitutive phosphorylation of Kit in cell culture (PMID: 16954519, PMID: 20633291, PMID: 27440273) despite reduced expression, enhanced degradation, and cellular mislocalization (PMID: 27440273).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|KIT D816V||Advanced Solid Tumor||resistant||Sunitinib||Preclinical||Actionable||In a preclinical study, KIT D816V mutations demonstrated resistance to Sutent (sunitinib) in a biochemical assay (PMID: 19164557).||19164557|