Activity Of Imatinib Mesilate In Metastatic Melanoma

KIT, a type III transmembrane receptor tyrosine kinase, plays a central role in cancer cell proliferation, invasion and metastases, through the activation of several signalling pathways. In melanocytes, KIT function is critical for the normal development and, in melanoma, it plays a predominant role as tumour suppressor. KIT gene alterations, as activating mutations or increased copy number, are relatively commonly demonstrated in melanomas arising in acral, mucosal and chronically sun-damaged sites. Over 21 different mutations of the KIT gene have been found; similar to GIST, the majority of these mutations occur within the juxtamembran authoinhibitory region encoded by exon 11. Some studies assessed that KIT could impact melanoma progression, suggesting that KIT-target therapies would be useful in advanced stage of disease. However, not all KIT mutations give the same responses to Imatinib. Despite the fact that L576P and K642E amino acid substitutions, that are the most common KIT alterations in melanomas, are more sensitive to KIT inhibitors, three phase 2 studies did not demonstrated clinical activity of Imatinib in treatment of unselected metastatic melanoma patients. In fact, only a subset of melanomas with genetic alteration of KIT responds to treatment, and genetic selection of KIT aberrations is a prerequisite for Imatinib-based therapy in metastatic melanoma. In this chapter are extensively explained the most recent literature data about the role of Imatinib in the treatment of metastatic melanoma; the mechanisms of treatment resistance and how to treat Imatinib-resistant patients are also discussed.