Opportunities and challenges in the development of kinase inhibitor therapy for cancer

Abstract

The success of the tyrosine kinase imatinib inhibitor (Gleevec, STI571) in treating chronic myeloid leukemia as well as other selected cancers has greatly increased optimism for the broader application of kinase inhibitor therapy in cancer. To date, however, imatinib remains the only spectacularly successful example. Is it simply a matter of time before kinase inhibitors become more broadly useful? Or is chronic myeloid leukemia a unique disease that does not reflect the true genetic complexity of other cancers? Here I address this question by summarizing the growing evidence that kinase inhibitor therapy works consistently and reliably against cancers in which the kinase drug target is constitutively activated by gene mutation. I also discuss the prospects for extending this concept more broadly—to other cancers in which kinase pathways are activated directly by kinase gene mutation or indirectly by loss of negative regulatory proteins (i.e., phosphatases such as the PTEN tumor suppressor). Finally, I give my perspective on how future drug discovery and clinical trial design programs in molecularly targeted therapy could be modified based on present clinical experience with kinase inhibitors.

Keywords

Affiliated Institutions

• University of California, Los Angeles US
• Howard Hughes Medical Institute US

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