Annotation Detail
Information
- Associated Genes
- KIT
- Associated Variants
-
KIT p.Asp817Glu (p.D817E)
(
ENST00000288135.6,
ENST00000412167.7,
ENST00000686011.1,
ENST00000687109.1,
ENST00000687246.1,
ENST00000687295.1,
ENST00000689832.1,
ENST00000689994.1,
ENST00000690543.1,
ENST00000692783.1 )
KIT p.Asp817Glu (p.D817E) ( ENST00000288135.6, ENST00000412167.7, ENST00000686011.1, ENST00000687109.1, ENST00000687246.1, ENST00000687295.1, ENST00000689832.1, ENST00000689994.1, ENST00000690543.1, ENST00000692783.1 ) - Associated Disease
- gastrointestinal stromal tumor
- Source Database
- CIViC Evidence
- Description
- Several preclinical studies were done in order to test the effects of various tyrosine kinase inhibitors (TKIs) on KIT-mutant cell lines derived from Gastrointestinal Stromal Tumor (GIST) patients with primary mutation 560-578 deletion and secondary mutation D816E. The cells were tested for Imatinib and Sunitinib resistances. GIST-T1/816 cells with 560-578 deletion and D816E mutations were resistant towards Imatinib and Sunitinib (Imatinib IC50: 604 nM and Sunitinib IC50: 3111 nM) compared to GIST-T1 cells with the 560-578 deletion mutation alone (Imatinib IC50: 30 nM and Sunitinib IC50: 15 nM). Imatinib inhibited phosphorylation in KIT and ERK at high concentrations. Sunitinib did not inhibit phosphorylation in KIT, ERK, or AKT at all. Additionally, Ba/F3 cells were mutagenized with N-ethyl-N-nitrosourea and incubated with varying concentrations of Sunitinib and Imatinib separately. In Imatinib incubated cells, D816E mutations were seen in less than 5% of resistant Ba/F3 cell clones only in the lowest concentration. In Imatinib incubated cells, D816E mutations were seen in approximately 10% of resistant Ba/F3 cell clones.
- Variant Origin
- somatic
- Variant Origin
- Somatic
- Evidence URL
- https://civic.genome.wustl.edu/links/evidence_items/4631
- Gene URL
- https://civic.genome.wustl.edu/links/genes/29
- Variant URL
- https://civic.genome.wustl.edu/links/variants/1559
- Rating
- 4
- Evidence Type
- Predictive
- Disease
- Gastrointestinal Stromal Tumor
- Evidence Direction
- Supports
- Drug
- Sunitinib,Imatinib
- Evidence Level
- D
- Clinical Significance
- Resistance
- Pubmed
- 25239608