KIT mutations in mastocytosis and their potential as therapeutic targets.

Deregulation of the KIT receptor TK by the prevalent activation loop mutation D816V has served as a focal point in therapeutic strategies aimed curbing neoplastic mast cell growth. Perhaps the most important development in this era of targeted therapy, and certainly relevant to KIT-driven diseases like mastocytosis, is the realization that small molecule inhibitors with varied chemical structure (eg, PKC412, dasatinib, AP23464) can circumvent the resistance of TKs to first-generation agents such as imatinib. Genuine opportunity now exists to effectively treat mastocytosis, and the arsenal consists of several orally bioavailable drugs with promising preclinical activity against D816V and other KIT mutants that promote mast cell growth. Because KIT mutations may not act as fully transforming oncogenic events in SM, it is prudent to evaluate combinations of TK inhibitors with drugs with activity in mast cell disease, such as cladribine, interferon-alpha, and corticosteroids. The identification of novel "drug-able" targets within mast cells should aid in the development of complementary therapies that promote enhanced cytotoxicity of mast cells through blockade of nonredundant signaling pathways. In addition, the generation of murine models that recapitulate human mastocytosis should accelerate preclinical testing of novel agents.