Reference Detail

Ref Type

Journal Article

PMID

(23567324)

Authors

Conca E, Miranda C, Dal Col V, Fumagalli E, Pelosi G, Mazzoni M, Fermeglia M, Laurini E, Pierotti MA, Pilotti S, Greco A, Pricl S, Tamborini E

Title

Are two better than one? A novel double-mutant KIT in GIST that responds to Imatinib.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular oncology	7	4	2013 Aug	756-62	Mol Oncol

URL

Abstract Text

Gastrointestinal stromal tumors carry in about 85% of the cases activating mutations in KIT gene. Generally only one KIT mutation is found in primary tumors and the majority of mutations affecting KIT exon 11 is sensitive to Imatinib. We report upon a GIST case harboring a double-mutant KIT gene at exon 11, which expresses a receptor bearing the known activating W557G mutation and a newly discovered missense Y578C alteration. The relative affinities for ATP and Imatinib of each single (W557G, Y578C) and double (W557G/Y578C) mutant KITs were predicted by in silico studies (computer-based molecular simulations), and compared with those obtained for known Imatinib sensitive and resistant KIT mutants. In parallel, biochemical analysis of the single and double KIT mutants expressed in mammalian cells was performed. Both the in-silico/in-vitro investigations showed constitutive activation and sensitivity to Imatinib of the yet mentioned Y578C mutation as well as of the double mutant, providing evidence that the concomitant presence of the W557G and Y578C mutations does not affect Imatinib response compare to the single mutations, in line with what observed in Imatinib treated patient.

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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	W557G	missense	gain of function - predicted	KIT W557G lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 16226710). W557G results in constitutive phosphorylation of Kit in cell culture (PMID: 23567324), and therefore, is predicted to lead to a gain of Kit protein function.
KIT	Y578C	missense	gain of function - predicted	KIT Y578C lies within the juxtamembrane domain (exon 11) of the Kit protein (PMID: 16226710). Y578C results in constitutive phosphorylation of Kit in cell culture (PMID: 23567324), and therefore, is predicted to lead to a gain of Kit protein function.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT W557C KIT Y578C	Advanced Solid Tumor	sensitive	Imatinib	Preclinical	Actionable	In a preclinical study, Gleevec (imatinib mesylate) inhibited Kit phosphorylation efficiently in transformed human cells over expressing both KIT W557C and KIT Y578C in culture (PMID: 23567324).	23567324
KIT Y578C	Advanced Solid Tumor	sensitive	Imatinib	Preclinical	Actionable	In a preclinical study, Gleevec (imatinib mesylate) inhibited Kit phosphorylation efficiently in transformed human cells over expressing KIT Y578C in culture (PMID: 23567324).	23567324
KIT W557G	Advanced Solid Tumor	sensitive	Imatinib	Preclinical	Actionable	In a preclinical study, Gleevec (imatinib mesylate) inhibited Kit phosphorylation efficiently in transformed human cells over expressing KIT W557G in culture (PMID: 23567324).	23567324