Inhibition of KIT Tyrosine Kinase Activity: A Novel Molecular Approach to the Treatment of KIT-Positive Malignancies

PURPOSE: Activation of the KIT tyrosine kinase by somatic mutation has been documented in a number of human malignancies, including gastrointestinal stromal tumor (GIST), seminoma, acute myelogenous leukemia (AML), and mastocytosis. In addition, paracrine or autocrine activation of this kinase has been postulated in numerous other malignancies, including small-cell lung cancer and ovarian cancer. In this review, we discuss the rationale for and development of KIT tyrosine kinase inhibitors for the treatment of human malignancies. MATERIALS AND METHODS: Studies were identified through a MEDLINE search, review of bibliographies of relevant articles, and review of abstracts from national meetings. RESULTS: Four tyrosine kinase inhibitors that have activity against KIT are currently being used in clinical trials, and one, STI571, has recently been approved by the United States Food and Drug Administration for treating patients with chronic myelogenous leukemia. The role of KIT inhibitors in treating KIT-positive malignancies is reviewed. CONCLUSION: Targeted therapy to inhibit the kinase activity of KIT is a rational approach to the treatment of KIT-positive malignancies. Two key factors are the potency of a given inhibitor and the relative contribution of KIT activation to the growth of the tumor. Given our current understanding of KIT activity in human malignancy, the best candidate diseases for treatment with KIT inhibitors are GIST, mastocytosis, seminoma and possibly some cases of AML. Additionally, KIT inhibitors may play an adjunctive role in diseases such as small-cell lung cancer, in which KIT activation is secondary to ligand binding rather than an acquired mutation.