Dasatinib Resistance in Patients with Chronic Myelogenous Leukemia: Identification of a Novel bcr-abl Kinase Domain Mutation

Abstract

Background

Dasatinib is a multi–tyrosine kinase–specific inhibitor with potent inhibitory activity against bcrabl kinase. It has been increasingly used in the treatment of imatinib-resistant chronic myelogenous leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia. However, despite its excellent activity, a proportion of patients present evidence of dasatinib resistance.

Patients and Methods

To assess the potential mechanisms of resistance, we have analyzed the bcr-abl kinase domain from 22 patients with CML who demonstrated clinical evidence of dasatinib failure.

Results

Mutations were present in 16 of 22 patients, and the majority were mapped to the adenosine triphosphate binding pocket. Of these, 7 had panresistant T315I, and 4 had F317L, with 1 F317I mutation. In addition, 3 of 16 patients evaluated had a V299L mutation. All of these mutations were previously reported in association with dasatinib resistance. We also observed that 1 of 7 patients in the chronic phase and 5 of 15 patients in the advanced phase had > 1 mutation in separate clones, as well as compound mutations (1 mRNA had ≥ 2 mutant codons). Interestingly, 4 of 15 patients with documented mutations were found to have a novel V304D mutation, which is located outside of the dasatinib binding site in the β 4-5 loop structure.

Conclusion

It appears that bcr-abl mutations in advanced-phase CML are more common but occur at lower frequencies in patients with chronic-phase disease (93% vs. 62%, respectively). Our results suggest that selection for T315I and F317L mutations occurs frequently in dasatinib-resistant patients, and both mutations were previously shown to affect dasatinib binding. Two additional mutations (V299L and V304D) have been identified with incidences that exceed random occurrence. The significance of these mutations is being evaluated.