Opportunities and challenges in the development of kinase inhibitor therapy for cancer (original) (raw)

  1. Charles L. Sawyers1
  2. Howard Hughes Medical Institute; Departments of Medicine, Molecular and Medical Pharmacology, and Urology; and Jonsson Cancer Center; David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA

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.

In May 2001, approval of the first tyrosine kinase inhibitor for the treatment of a human cancer (imatinib/Gleevec for chronic myeloid leukemia) was greeted with great optimism by the oncology community, with hopes for successful extension of this approach to other malignancies. One year later, the failure of a second tyrosine kinase inhibitor (gefitinib/Iressa), when combined with chemotherapy, to show superiority to standard treatment for lung cancer led to reservations about the promise of kinase inhibitors as anticancer agents. This review is my perspective on where we stand. Building on my experience with the development of imatinib for chronic myeloid leukemia, I summarize why I believe some clinical trials with this class of drugs have succeeded whereas others have failed. …