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Signal Transduction Inhibitors in Chronic Myeloid Leukemia

  • Michael W. N. Deininger
Part of the Hematologic Malignancies book series (HEMATOLOGIC)

Abstract

Chronic myeloid leukemia (CML) is caused by Bcr-Abl, a constitutively active tyrosine kinase that activates multiple signaling pathways and is central to disease pathogenesis. Efforts to develop small molecule Bcr-Abl inhibitors led to the discovery of imatinib, a 2-phenylaminopyrimidine that inhibits Bcr-Abl with high selectivity and has rapidly become standard therapy for CML. Responses in newly diagnosed chronic phase patients tend to be durable, but there is a high relapse rate in advanced disease, which is mostly due to point mutations in critical residues that interfere with drug binding, thereby reactivating Bcr-Abl. The fact that Bcr-Abl remains central to disease pathogenesis has stimulated a search for novel Abl kinase inhibitors with activity against mutant Bcr-Abl. Nilotinib, developed from an imatinib backbone, and dasatinib, a dual Abl/Src kinase inhibitor, are currently in phase I/II clinical trials of patients with imatinib-resistant CML, with very encouraging results. While Bcr-Abl is the most attractive target, there are multiple signal transduction pathways downstream that can be intercepted with specific inhibitors, such as blockers of farnesyl transferase and mTOR. Some of these compounds are in clinical trials of imatinib-resistant patients, but results are not yet available. Although imatinib is probably not capable of eradicating CML stem cells, for many patients this agent has turned a life-threatening disease into a chronic disorder that does not significantly affect quality of life.

Keywords

Chronic Myeloid Leukemia Imatinib Mesylate Signal Transduction Inhibitor Farnesyl Transferase Inhibitor Myeloid Blast Crisis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Berlin Heidelberg 2007

Authors and Affiliations

  • Michael W. N. Deininger
    • 1
  1. 1.Center for Hematologic MalignanciesOregon Health & Science UniversityPortlandUSA

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