Journal
DRUG RESISTANCE UPDATES
Volume 12, Issue 1-2, Pages 8-16Publisher
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.drup.2008.12.001
Keywords
AML; Combination therapy; Multitargeted agents; NF-kappa B inhibition; Leukemic stem cells; PKC412; MLN518; SU-5416; SU11248; KW-2449; AC220; CEP701
Categories
Funding
- NCI [CA90668, CA70970]
- Leukemia and Lymphoma Society
- Children's Cancer Foundation
- Burroughs-Wellcome Fund
- Kyle Haydock Professorship
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The success of the small molecule tyrosine kinase receptor inhibitor (TKI) imatinib mesylate (Gleevec) in the treatment of chronic myeloid leukemia (CML) constitutes an eminent paradigm shift advocating the rational design of cancer therapeutics specifically targeting the transformation events that drive tumorigenicity. In acute myeloid leukemias (AMLs), the most frequent identified transforming events are activating mutations in the FLT3 receptor tyrosine kinase that constitutively activate survival and proliferation pathways. FLT3 TKIs that are in various phases of clinical trials are showing some initial promise. However, primary and secondary acquired resistance stands to severely compromise long-term and durable efficacy of these inhibitors as a therapeutic strategy. Here, we discuss the mechanisms of resistance to FLT3 inhibitors and possible strategies to overcome resistance through closer examination of the events of leukemogenesis and design of combination therapy. (c) 2008 Elsevier Ltd. All rights reserved.
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