• Thomas O'Hare, Michael W N Deininger, Christopher A Eide, Tim Clackson, and Brian J Druker.
• Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon, USA. oharet@ohsu.edu
• Clin Cancer Res. 2011 Jan 15; 17 (2): 212-21.

AbstractBeginning with imatinib a decade ago, therapy based on targeted inhibition of the BCR-ABL kinase has greatly improved the prognosis for chronic myeloid leukemia (CML) patients. The recognition that some patients experience relapse due to resistance-conferring point mutations within BCR-ABL sparked the development of the second-generation ABL kinase inhibitors nilotinib and dasatinib. Collectively, these drugs target most resistant BCR-ABL mutants, with the exception of BCR-ABL(T315I). A third wave of advances is now cresting in the form of ABL kinase inhibitors whose target profile encompasses BCR-ABL(T315I). The leading third-generation clinical candidate for treatment-refractory CML, including patients with the T315I mutation, is ponatinib (AP24534), a pan-BCR-ABL inhibitor that has entered pivotal phase 2 testing. A second inhibitor with activity against the BCR-ABL(T315I) mutant, DCC-2036, is in phase 1 clinical evaluation. We provide an up-to-date synopsis of BCR-ABL signaling pathways, highlight new findings on mechanisms underlying BCR-ABL mutation acquisition and disease progression, discuss the use of nilotinib and dasatinib in a first-line capacity, and evaluate ponatinib, DCC-2036, and other ABL kinase inhibitors with activity against BCR-ABL(T315I) in the development pipeline.©2010 AACR.

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