A new clinical study shows encouraging results with a novel BCR–ABL inhibitor, including in leukemia patients with therapy-resistant mutations (N. Engl. J. Med. 367, 2075–2088, 2012).

Imatinib, a BCR–ABL kinase inhibitor, has become the standard of treatment for patients with chronic myeloid leukemia (CML), and it epitomizes the successes and shortcomings of targeted therapy. Although the continuous use of this drug provides durable responses in many patients, secondary resistance can arise, driven by acquired mutations in the ABL kinase domain that preclude imatinib binding. Second-generation inhibitors have been efficacious in some resistant patients but are still powerless against emblematic gatekeeper mutations.

A third-generation kinase inhibitor, ponatinib, was recently developed and showed efficacy in cells expressing a resistant mutant version of the oncogenic BCR–ABL fusion. Now, Jorge E. Cortes et al. report their phase I trial results of this drug, which suggest that it has clinical promise for the treatment of relapsed disease. The multicenter dose-escalation trial included 81 patients with different stages of BCR–ABL-positive hematological cancer and who had not responded to first- or second-generation kinase inhibitors.

The study determined a maximum tolerated dose and the safety profile of the drug but, interestingly, also reports significant hematologic and cytogenetic responses in chronic-phase patients, as well as responses in a subset of patients with advanced disease.

Importantly, ponatinib is active against a range of resistant mutations, illustrating the potential of rational drug design to overcome the dynamic hurdles of cancer therapy resistance and bringing new hope to patients with CML.