Annotation Detail

Information
Associated Genes
ALK
Associated Variants
ALK p.Phe1174Leu (p.F1174L) ( ENST00000389048.8, ENST00000618119.4, ENST00000642122.1 )
ALK p.Phe1174Leu (p.F1174L) ( ENST00000618119.4, ENST00000642122.1, ENST00000389048.8 )
Associated Disease
neuroblastoma
Source Database
CIViC Evidence
Description
Efficacy of the second generation ALK inhibitor PF-06463922 was tested on ALK mutation F1174L containing neuroblastoma-derived cells. COG-N-453x and SH-SY5Y xenografts showed some inhibition when treated with crizotinib, but showed complete growth inhibition with PF-06463922 treatment. This corresponded to 0% event free survival (EFS) in these mice by 6 weeks with crizotinib treatment, but 100% EFS with PF-06463922 treatment. Comparison of crizotinib and PF-06463922 growth inhibition in F1174L cells SH-SY5Y, NBSD 415-IMDM and KELLY showed increased sensitivity to PF-06463922, as compared to crizotinib. Inhibition effects were not seen on neuroblastoma cells with wild type ALK (NB-EBc1, SK-N-BE(2)C). Decreased phosphorylation on ALK tyrosine 1278 was seen with PF-06463922 over crizotinib at 10 and 100 nM concentrations in SH-SY5Y cells. PF-06463922 was well tolerated in the in-vivo models.
Variant Origin
somatic
Variant Origin
Somatic
Evidence URL
https://civic.genome.wustl.edu/links/evidence_items/1329
Gene URL
https://civic.genome.wustl.edu/links/genes/1
Variant URL
https://civic.genome.wustl.edu/links/variants/8
Rating
4
Evidence Type
Predictive
Disease
Neuroblastoma
Evidence Direction
Supports
Drug
Lorlatinib
Evidence Level
D
Clinical Significance
Sensitivity/Response
Pubmed
26554404
Drugs
Drug NameSensitivitySupported
LorlatinibSensitivitytrue