c-Kit Mutations and Their Role in Tumor Biology

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DESCRIPTION (provided by applicant): Mast cell tumors (MCTs) are the most frequently diagnosed malignant tumor of the dog. We have previously demonstrated that at least 30% of canine MCTs possess mutations in the proto-oncogene c-kit consisting of tandem duplications in exons 11/12 encoding the negative regulatory juxtamembrane domain. These mutations result in constitutive phosphorylation of Kit in the absence of ligand binding. Dysregulation of Kit has also been found to occur in many human tumors including aberrant expression (small cell lung carcinoma, genitourinary cancers) and mutation in the cytoplasmic domain leading to constitutive activation (mast cell disorders, gastrointestinal stromal tumors). Recent studies with various experimental kinase inhibitors suggest that inhibition of Kit signaling may be of significant benefit to patients with these malignancies. However, for their application to be successful, it is critical that the role of c-kit mutations in the initiation and progression of neoplastic disorders be more clearly defined. The hypothesis underlying this proposal is that activating mutations of c-kit are associated with the development and progression of malignant mast cell disease through the promotion of cell survival and induction of metalloproteinase gene expression linked to invasion and metastasis. The specific aims of this study are: 1) to undertake a meticulous characterization of c-kit mutations in dog MCTs including their impact on the biologic behavior of MCTs, and identification of potential risk factors associated with their development; 2) to study the effect of Kit dysregulation on normal cell populations in vivo through the generation of transgenic mice expressing various forms of mutant c-kit under a highly regulated inducible promoter; and 3) to evaluate the effects of indolinone kinase inhibitors on dysregulated Kit both in vitro and in mouse models of Kit mutation. The integration of detailed investigations of Kit dysregulation in the mouse with comprehensive studies of a spontaneous model of c-kit mutation in the dog will help to clarify the biological and biochemical consequences of such mutations. Moreover, the incorporation of kinase inhibitors into these studies offers a unique opportunity to evaluate the potential usefulness and efficacy of such agents in the treatment of neoplastic diseases in which Kit dysfunction is evident.