Annotation Detail
Information
- Associated Genes
- KRAS
- Associated Variants
-
KRAS p.Gly12Cys (p.G12C)
(
ENST00000256078.10,
ENST00000311936.8,
ENST00000556131.2,
ENST00000557334.6,
ENST00000685328.1,
ENST00000686969.1,
ENST00000688940.1,
ENST00000692768.1,
ENST00000693229.1 )
KRAS p.Gly12Cys (p.G12C) ( ENST00000256078.10, ENST00000311936.8, ENST00000556131.2, ENST00000557334.6, ENST00000685328.1, ENST00000686969.1, ENST00000688940.1, ENST00000692768.1, ENST00000693229.1 ) - Associated Disease
- cancer
- Source Database
- CIViC Evidence
- Description
- Preclinical study to investigate mechanisms of KRAS G12C activity and inhibition with ARS-853, a covalent (irreversible) inhibitor which binds KRAS G12C in the GDP-bound state to prevent activation. Results from a mass spectrometry-based assay to evaluate KRAS activity suggests that G12C mutant KRAS is in a “hyperexcitable” rather than a “statically active” state. ARS-853 targets the inactive state and inhibited proliferation in a subset (3/11) of KRAS G12C mutant cell lines in 2-D growth assays and 11/11 cell lines in soft-agar colony formation and 3-D assays. This effect was specific for KRAS G12C as 12/12 cell lines with other KRAS mutations (including other G12 mutations V, D and A) were not inhibited in either soft-agar assay. Relative resistance to ARS-853 developed after epidermal growth factor (50 ng/mL) administration and the combination of erlotinib or afatinib (EGFR-inhibitors) with ARS-853 greatly potentiated growth arrest, apoptosis and decrease of PI3K and MAPK-signaling over single-agent ARS-853 treatment, even in the presence of added EGF.
- Variant Origin
- somatic
- Variant Origin
- Somatic
- Evidence URL
- https://civic.genome.wustl.edu/links/evidence_items/1173
- Gene URL
- https://civic.genome.wustl.edu/links/genes/30
- Variant URL
- https://civic.genome.wustl.edu/links/variants/78
- Rating
- 3
- Evidence Type
- Predictive
- Disease
- Cancer
- Evidence Direction
- Supports
- Drug
- ARS-853,Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor
- Evidence Level
- D
- Clinical Significance
- Sensitivity/Response
- Pubmed
- 26739882
Drugs
| Drug Name | Sensitivity | Supported |
|---|---|---|
| ARS-853 | Sensitivity | true |
| Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor | Sensitivity | true |