KIT-Mutant Melanoma: Understanding the Pathway to Personalized Therapy

Melanoma is a highly heterogeneous disease, with unique genetic subtypes that influence clinical behavior and treatment response. While targeted therapies and immunotherapy have transformed care for more common types of melanoma, optimal strategies for KIT-mutant melanoma are less well-defined. In this review, we summarize the associations between KIT mutations and specific clinico-pathologic patterns, including their enrichment in acral, mucosal, and chronically sun-damaged melanomas. We detail the spectrum of KIT mutations across relevant exons, noting how mutation subtype influences sensitivity to targeted therapies. We will then analyze several therapeutic trials and case reports that describe the use of c-KIT inhibitors as well as immune checkpoint inhibitors in melanoma treatment. We also discuss early findings supporting combination strategies that may enhance therapeutic outcomes. Finally, we identify critical gaps in understanding the mechanisms of resistance, CNS progression, and the immunogenic landscape of KIT-driven melanoma. Deeper insight into the function of KIT and its interaction with therapeutic pathways is essential to optimizing treatment sequencing and tailoring personalized strategies that improve outcomes in this patient population.