Improving upon the promise of targeted therapy of human malignancy: chronic myeloid leukemia as a paradigm
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- Shah, N.P. Cancer Chemother Pharmacol (2006) 58: 49. doi:10.1007/s00280-006-0316-4
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The small molecule BCR-ABL-selective kinase inhibitor imatinib is the single most effective medical therapy for the treatment of chronic myeloid leukemia (CML). Although imatinib is highly effective initially and generally well tolerated, for patients who undergo relapse or disease progression few effective therapeutic options exist. Studies have demonstrated that the principal mechanisms of imatinib resistance are BCR-ABL kinase domain point mutation and over-expression. Two novel, potent BCR-ABL inhibitors that harbor promising preclinical activity are undergoing clinical trial evaluation. These agents, dasatinib (BMS-354825) and nilotinib (AMN107), effectively inhibit the activity of nearly all imatinib-resistant BCR-ABL kinase domain mutant forms tested in vitro. Notably, however, neither of these compounds is effective against the imatinib-resistant BCR-ABL/T315I mutation. Early clinical evidence suggests that the T315I mutation might drive the majority of cases who acquire resistance to these second-generation agents. Preclinical efforts to identify an inhibitor of the BCR-ABL/T315I mutation have resulted in demonstration that the Aurora kinase inhibitor VX-680 can bind and inhibit the kinase domain of BCR-ABL/T315I.