Annotation Detail

Information
Associated Genes
ALK
Associated Variants
ALK EML4-ALK E6;A20
Associated Disease
lung non-small cell carcinoma
Source Database
CIViC Evidence
Description
Ceritinib was 28x more potent (GI50 3.8nM) than crizotinib (GI50 107nM) at inhibiting growth of H2228, an NSCLC cell line which harbors the EML4-ALK variant 3a/3b. SCID mice xenografted with H2228 were treated for 14 days with crizotinib (100 mg/kg) or ceritinib (25 or 50 mg/kg). All treatments caused tumor regression, but tumors recurred within 11 days after crizotinib treatment withdrawal. 4/8 mice treated with 25 mg/kg ceritinib showed regrowth after 1 month treatment withdrawal. The remaining 4/8 mice treated at 25 mg/kg ceritinib, and all mice treated at 50 mg/kg ceritinib maintained complete remission for four months. While 100 mg/kg crizotinib in mice approximates levels 3-5 times the maximal tolerated dose in humans, the authors state 25 to 50 mg/kg ceritinib in mice is predicted to approximate tolerable doses in humans.
Variant Origin
somatic
Variant Origin
Somatic
Evidence URL
https://civic.genome.wustl.edu/links/evidence_items/1340
Gene URL
https://civic.genome.wustl.edu/links/genes/1
Variant URL
https://civic.genome.wustl.edu/links/variants/503
Rating
3
Evidence Type
Predictive
Disease
Lung Non-small Cell Carcinoma
Evidence Direction
Supports
Drug
Ceritinib
Evidence Level
D
Clinical Significance
Sensitivity/Response
Pubmed
24675041
Drugs
Drug NameSensitivitySupported
CeritinibSensitivitytrue