Treatment recommendations based on BCR-ABL1 mutation profile...The table below lists the BCR-ABL1 mutations that should not be treated with bosutinib, dasatinib or nilotinib in the second-line setting…Dasatinib…T315I/A, F317L/V/I/C, or V299L
Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase
Mutations were identified in 60 (60%) of these patients (all with imatinib-resistant CML-AP). Despite the presence of imatinib-resistant BCR-ABL mutations and their association with poor prognosis, at 8 months' follow-up, 73% of patients with an imatinib-resistant BCR-ABL mutation had achieved MaHR following treatment with dasatinib.
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
At 5 nM dasatinib mutations of L248, Q252, E255, V299, T315, and F317 were recovered (Table 1)….Spectrum and frequency of BCR-ABL kinase domain mutations recovered in the presence of imatinib mesylate, nilotinib, and dasatinib.
Activity of Bosutinib, Dasatinib, and Nilotinib Against 18 Imatinib-Resistant BCR/ABL Mutants
In our study, we investigated the activity of bosutinib, dasatinib, imatinib, and nilotinib against a panel of 18 mutated forms of BCR/ABL associated with imatinib resistance in CML and Ph+ acute lymphoblastic leukemia patients. The results are listed in Figure 1 (Table 1 lists all the actual values for the relative concentration that inhibits 50%).
Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance
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.