Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain

Abstract

The emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelphia chromosome-positive (Ph+) leukemia has prompted the development of second-generation compounds active against several imatinib-insensitive mutant forms of Bcr-Abl, including dasatinib (BMS-354825; Bristol-Myers Squibb). In order to assess which pre-existent or emerging kinase domain mutations are associated with decreased clinical efficacy of desatinib, we analyzed BCR-ABL kinase sequences before and during treatment in 21 Ph+ patients who failed to respond to or relapsed during dasatinib therapy. In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317.