As we enter the era of targeted therapy, it is vital to subgroup tumors on the basis of their driving oncogenic mutations so that appropriate therapeutic agents can be developed. The majority of melanomas possess activating mutations in BRAF, which promotes activation of the mitogen-activated protein kinase (MAPK) signaling pathway. However, there are distinct subtypes of melanoma including chronic sun damaged (CSD), acral, and mucosal that rarely harbor BRAF mutations. Alterations in c-KIT have been identified as the most common oncogenic event in these melanoma subtypes. Therefore, therapeutic targeting of c-KIT has recently gained interest. Although several phase II clinical trials with an inhibitor of c-KIT (imatinib) in unselected melanoma patients proved disappointing, recent reports highlight dramatic responses in patients diagnosed with mucosal melanomas that possessed c-KIT alterations.
c-KIT is a receptor tyrosine kinase (RTK) that is responsible for growth regulation, differentiation, proliferation and migration in melanocytes. Binding of the c-KIT ligand, stem cell factor (SCF), results in receptor dimerization and autophosphorylation, which initiates activation of downstream signaling cascades including RAS/MAPK, phosphoinositide-3 kinase (PI3K)/AKT, janus kinase (JAK)/signal transducers and activators of transcription (STAT), and phospholipase-C (PLC). c-KIT gain-of-function mutations allow for receptor activation in the absence of SCF and have been identified in the majority of gastrointestinal stromal tumors (GIST), seminomas, and adenoid cystic carcinomas. Treatment of recurring GIST with the small molecule c-KIT inhibitor imatinib results in an overall objective clinical benefit and provides a significant survival advantage for most patients.
In addition to high level c-KIT amplification, a diverse set of activating mutations in multiple exons have recently been identified in melanoma patient samples. The oncogenic capacity of these mutants and responsiveness to imatinib or similar inhibitors remains to be fully characterized. Clarification of these elements will result in better patient selection and likely improve response rates. To this end, we are currently evaluating the ability of c-KIT mutants singly and in combination with other cooperating genomic alterations to promote melanoma initiation and/or progression in our recently described melanoma mouse model based on RCAS/TVA.