ABSTRACT

Constitutively activated tyrosine kinases have been investigated for decades now for their role in the pathogenesis of different cancers. The importance of these oncogenes in oncogenesis is no longer a subject of debate. Still being debated, however, is how effectively these enzymes can be targeted and whether or not such targeting will have a meaningful impact in treating these diseases. Tyrosine kinases, in particular, seem to be important in the development of hematologic malignancies, especially myeloid leukemias. Starting with the recognition that the product of the Philadelphia chromosome (Bcr-Abl) is an activated tyrosine kinase, to the recent discovery of a PDGFRα fusion protein in hypereosinophilic syndrome (HES) and eosinophilic leukemia, and a gain of function mutation of Janus Kinase 2 (JAK2), mutation-activated kinases continue to be identified as causative factors in hematopoietic disorders (1–5). The first successful clinical use of a small molecule kinase inhibitor, imatinib, was, in fact, in the treatment of chronic myelogenous leukemia (CML) (6). Small molecule kinase inhibitors represent a new, rapidly expanding class of anticancer drugs. Seven different kinase inhibitors have been approved for the treatment of a variety of malignancies since 2001, and many more are under development (7–13). Their use, particularly in patients with activating kinase mutations, often results in dramatic 380clinical responses. Survival is frequently improved, although, with the exception of imatinib in CML, the responses are usually not durable. The targets of these agents are not necessarily known. While all of them are developed with a specific molecular target in mind, some exert their clinical effects through inhibition of either unknown or unanticipated targets. This has led to enthusiasm for multitargeted inhibitors that have activity against a broad array of biologically relevant kinases. Dasatinib, for example, is a potent inhibitor of both imatinib-resistant forms of Bcr-Abl and also of Src-family kinases.