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Association details:
| Biomarker: | BCR-ABL1 L248R |
|---|---|
| Cancer: | Chronic Myeloid Leukemia |
| Drug: | dasatinib (c-KIT inhibitor, Bcr-abl tyrosine kinase inhibitor, Src kinase inhibitor, EphA2 receptor antagonist, PDGFR β antagonist) |
| Direction: | Resistant |
Evidence:
Source:
Title:
Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)–based mutagenesis screen: high efficacy of drug combinations
Excerpt:
Overall, these data indicate that the ENU-based assay faithfully reproduces the spectrum of mutations seen in patients with clinical resistance to imatinib mesylate...Spectrum and frequency of BCR-ABL kinase domain mutations recovered in the presence of imatinib mesylate, nilotinib, and dasatinib...Although both dasatinib and nilotinib are much more potent than imatinib mesylate and have activity against most kinase domain mutants, it is conceivable that their specific modes of binding to Abl may lead to new “vulnerable” sites that could confer drug resistance.
DOI:
10.1182/blood-2006-02-004580
Source:
Title:
Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance
Excerpt:
To examine the potential role of conformational binding properties in drug resistance, we mapped the mutations in BCR-ABL capable of conferring resistance to BMS-354825....T315I conferred the greatest degree of resistance to BMS-354825 with an IC50 >750-fold over WT BCR-ABL. T315A and F317V, two previously uncharacterized mutants, show the next highest IC50s, 40- to 90-fold over WT.
DOI:
10.1073/pnas.0409770102
