Kit mutations in cancer and their treatment with protein kinase inhibitors

The Kit receptor, or the receptor for stem cell factor (SCIF), is a member of the type III subclass of receptor tyrosine kinases (RTKs). Signaling by SCIF and Kit plays an important role in hematopoiesis, gametogenesis, melanogenesis and mast cell development and function. Kit is frequently activated in neoplastic diseases; in fact, more than 30 gain-of-function mutations in Kit, either single amino acid changes or small deletions/insertions, have been identified in various tumors, including gastrointestinal stromal tumors (GISTs), mastocytosis, acute leukemias, melanomas and other cancers. Targeting of Kit by imatinilb mesilate, a TK inhibitor, was found to be an effective anticancer strategy for the treatment of GISTs. However, the occurrence during treatment of secondary mutations of Kit renders the tumors resistant to imatinib. A growing generation of second-line TK inhibitors, such as nilotinib and dasatinib, are active against imatinib-resistant Kit mutant cancers and could thus offer a valuable therapeutic strategy. Non-TK inhibitors like rapamycin, 17-AAG and IMD-0354 have been added to the therapeutic armamentarium, with the hope that their use in combination therapy might have a synergistic antitumor effect or prevent/delay the development of drug resistance.