Annotation Detail

Information
Associated Genes
ABL1
Associated Variants
ABL1 p.Arg351Trp (p.R351W) ( ENST00000318560.6, ENST00000372348.9 )
ABL1 p.Arg351Trp (p.R351W) ( ENST00000318560.6, ENST00000372348.9 )
Associated Disease
lung non-small cell carcinoma
Source Database
CIViC Evidence
Description
In this in vitro study, the H1915 non-small cell lung cancer cell line (homozygous for a R351W mutation) was shown to be susceptible to imatinib. This line showed a significant reduction in colony formation (P = 0.0004) and MTT assay, which tests for NADH activity (P < 0.001), with imatinib vs vehicle treatment. There was no significant difference in a lung cancer cell line without a known driver (H2126) nor in an immortalized bronchial epithelial line (Beas-2B) with either drug treatment in colony forming and MTT assays. Additionally, reduction in cell viability upon kinase inhibitor treatment was rescued with tetracycline-induced overexpression of resistant ABL1-T315I (P < 0.001) confirming the genetic dependency of this cell line on ABL1. Moreover, siRNA facilitated depletion of ABL1 expression resulted in significantly increased cytotoxicity (P < 0.004) with no significant change in H2126 or Beas-2B lines for 2/3 siRNAs supporting ABL1 as the primary drug target. Significant tumor reduction was observed in murine NSCLC xenografts of the H1915 cell line treated with imatinib compared to vehicle treatment (P = 0.0016). No change in tumor growth was observed in xenografts of the H650 cell line containing a wildtype ABL1 locus. In both in vitro and in vivo experiments, doxycycline-inducible expression of drug-resistant ABL1-T315I rescued imatinib-mediated inhibitory effects supporting the specificity of drug responses.
Variant Origin
somatic
Variant Origin
Somatic
Evidence URL
https://civic.genome.wustl.edu/links/evidence_items/6376
Gene URL
https://civic.genome.wustl.edu/links/genes/4
Variant URL
https://civic.genome.wustl.edu/links/variants/1656
Rating
5
Evidence Type
Predictive
Disease
Lung Non-small Cell Carcinoma
Evidence Direction
Supports
Drug
Imatinib
Evidence Level
D
Clinical Significance
Sensitivity/Response
Pubmed
26758680
Drugs
Drug NameSensitivitySupported
ImatinibSensitivitytrue