Although only 5000 new cases of chronic myeloid leukemia (CML) were seen in the United States in 2009, this neoplasm continues to make scientific headlines year-after-year. Advances in understanding the molecular pathogenesis coupled with exciting developments in both drug design and development, targeting the initiating tyrosine kinase, have kept CML in the scientific limelight for more than a decade. Indeed, imatinib, a small-molecule inhibitor of the leukemia-initiating Bcr–Abl tyrosine kinase, has quickly become the therapeutic standard for newly diagnosed chronic phase-CML (CP-CML) patients. Yet, nearly one-third of patients will still have an inferior response to imatinib, either failing to respond to primary therapy or demonstrating progression after an initial response. Significant efforts geared toward understanding the molecular mechanisms of imatinib resistance have yielded valuable insights into the cellular biology of drug trafficking, enzyme structure and function, and the rational design of novel small molecule enzyme inhibitors. Indeed, new classes of kinase inhibitors have recently been investigated in imatinib-resistant CML. Understanding the pathogenesis of tyrosine kinase inhibitor resistance and the molecular rationale for the development of second and now third generation therapies for patients with CML will be keys to further disease control over the next 10 years.
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Bixby, Dale MD PhD reports that he is on the speakers bureau for Novartis. Talpaz, Moshe MD reports that he is on the speakers bureau for Novartis and receives grant support from Novartis, Bristol-Myers Squibb, Exelixis and Merck.
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Bixby, D., Talpaz, M. Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia. Leukemia 25, 7–22 (2011). https://doi.org/10.1038/leu.2010.238
- chronic myeloid leukemia
- tyrosine kinase inhibitors
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