c-Kit was initially characterized on the basis of an oncogenic variant, i.e., v-kit (10). As with many cytokine/growth factor receptors, numerous reports of c-kit expression on different types of tumor cells have appeared (e.g., mastocytosis, gastrointestinal stromal tumor (GIST), AML, seminoma, small-cell lung cancer [SCLC], ovarian carcinoma, breast cancer, and melanoma [195-197]). It is apparent that many of these tumors derive from tissues that normally express c-kit. YB5.B8, the first monoclonal Ab against c-kit (unbeknownst at the time) was raised as an antitumor-Ag Ab using AML cells as immunogen (8).

For two relatively rare tumor types, mastocytoma and GIST, c-kit is highly expressed in almost all cases and is usually mutationally altered such that the c-kit kinase is constitutively activated (32,168,189,195). Most adult-onset mastocytomas have the D816V mutation, an activating mutation situated near the kinase active site. Most GISTs have mutations in the cytoplasmic juxtamembrane region, representing a putative amphipathic a-helix thought to regulate c-kit kinase activity negatively. c-Kit is expressed in most cases of AML (earlier stage blasts) and seminoma, and activating mutations occur, albeit infrequently (195). For these and other tumors (e.g., SCLC) expressing c-kit that is not mutationally activated, functional activation of c-kit by SCF (autocrine or paracrine) has frequently been shown in vitro, but whether or not such activation contributes to in vivo tumorgenicity remains unclear.

The recent introduction of potent small-molecule kinase inhibitors (of varying mechanisms, potencies, and specificities) into clinical testing and practice has focused attention on c-kit-expressing tumors, particularly GIST. STI571 (imatinib), a potent inhibitor of the chronic myelogenous leukemia (CML) BCR-ABL fusion protein kinase, has achieved impressive clinical results in the CML setting (195). STI571 potently inhibits PDGFR kinase activity and c-kit kinase activity, and early clinical testing in the GIST

setting has been promising (195,198,199). At the doses used, STI571 generally does not produce side effects reflecting action on other c-kit-dependent cell types. STI571 does not inhibit c-kit activated by the D816V mutation and therefore is unlikely to be clinically effective in the mastocytoma setting. Other inhibitors may prove effective as single agents in mastocytosis. Clinical studies with inhibitors that potentially target c-kit kinase activity have been initiated in the c-kit+ AML setting (195). It may be that for AML and other c-kit-expressing tumors in which c-kit kinase is not mutationally activated, the contributions of the SCF/c-kit axis to tumorgenesis are minimal or partial, but c-kit kinase inhibitors could find clinical use in combination with other anticancer agents.

c-Kit tends to be expressed in the early stages of melanomas and breast cancers but is downregulated with tumor progression (196,197). The transcription factor AP-2 can activate c-kit expression, and in the case of melanomas, the downregulation of c-kit appears to be secondary to loss of AP-2. Ectopic expression of AP-2 or c-kit in advanced-stage melanoma cells can inhibit their growth and metastasis in models in vivo and can increase their susceptibility to SCF-induced apoptosis in vitro (200,201).

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