KIT as an Oncogenic Driver in Melanoma: An Update on Clinical Development

Metastatic melanoma is a heterogenous disease that has served as a model for the development of both targeted therapy and immunotherapy. KIT-mutated melanoma represents a rare subset, most commonly arising from acral, mucosal, and chronically sun-damaged skin. Additionally, KIT alterations are enriched in the triple wild-type subtype of cutaneous melanoma. Activating alterations of KITa transmembrane receptor tyrosine kinase important for cell development, growth, and differentiationhave been shown to be critical to oncogenesis across many tumor subtypes. Following the successes of BRAF-targeted therapy in melanoma and KIT-targeted therapy in gastrointestinal stromal tumors, small-molecule tyrosine kinase inhibitors targeting KIT have been examined in KIT-mutated melanoma. KIT inhibitors that have been investigated in relevant clinical trials in advanced melanoma include imatinib, sunitinib, dasatinib, and nilotinib. In these studies, selected patients with KIT-mutated melanoma were shown to be responsive to therapy with KIT inhibition, especially patients with L576P and K642E mutations. This has led to the incorporation of KIT-targeted therapy in the National Comprehensive Cancer Network guidelines for systemic therapy for metastatic or unresectable melanoma. Current research and development efforts include novel KIT-targeted therapies and testing KIT inhibitors in combination with immunotherapy.