期刊
CLINICAL CANCER RESEARCH
卷 17, 期 2, 页码 212-221出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-09-3314
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- NCI NIH HHS [R37 CA065823] Funding Source: Medline
Beginning 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. Clin Cancer Res; 17(2); 212-21. (C)2010 AACR.
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