Starting April 21, you’ll be asked to log in or sign up for a free account after viewing 10 content pages each month.
Don’t worry—creating an account is quick and easy, and it comes with added benefits! Once logged in, you’ll not only continue accessing the content you already enjoy, but you’ll also unlock exclusive features like interactive donut plots for variant protein effects and variant impacts across the gene.
Stay tuned for these updates, and thank you for being part of our community!
Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : ckbsupport@genomenon.com
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. | ||||||||||||
|
|||||||||||||
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. |
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 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 |
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 |