Annotation Detail

Information
Associated Genes
FLT3
Associated Variants
FLT3 ITD
FLT3 ITD
Associated Disease
acute myeloid leukemia
Source Database
CIViC Evidence
Description
In a preclinical trial, multiple experiments testing the effectiveness of ponatinib on the mutation FLT3-ITD in acute myeloid leukemia (AML) were conducted. Ponatinib was very effective in targeting the FLT3-ITD mutation in MV4-11 cell lines (growth inhibition: IC50=2 nmol/L) compared to native FLT3 in RS4;11 cell lines (IC50>100 nmol/L). Additionally, MV4-11 cell lines incubated for 1 hour were shown to have reduced phosphorylation of tyrosine kinases beginning at a ponatinib concentration of 0.3 nmol/L. Ponatinib was shown to induce apoptotic mechanisms measured by caspase-3/7 activity in MV4-cell lines. In mice with the MV4-11 xenograft, ponatinib was very effective in targeting the FLT3-ITD mutation, as dosages of 1-5 mg/kg led to tumor growth inhibition and regression, while dosages of 10 and 25 mg/kg led to complete tumor regression. In primary blast cells from AML patients, Ponatinib was selectively effective in growth inhibition of the FLT3-ITD patient cells (n=1, IC50=4nmol/L) when compared to the native FLT3 patient cells (n=3, IC50>100nmol/L).
Variant Origin
somatic
Variant Origin
Somatic
Evidence URL
https://civic.genome.wustl.edu/links/evidence_items/7369
Gene URL
https://civic.genome.wustl.edu/links/genes/24
Variant URL
https://civic.genome.wustl.edu/links/variants/55
Rating
5
Evidence Type
Predictive
Disease
Acute Myeloid Leukemia
Evidence Direction
Supports
Drug
Ponatinib
Evidence Level
D
Clinical Significance
Sensitivity/Response
Pubmed
21482694
Drugs
Drug NameSensitivitySupported
PonatinibSensitivitytrue