Despite significant progress in melanoma research, from prevention, detection, and diagnosis to treatment, the incidence of melanoma continues to rise dramatically and 5-year survival for those with advanced disease remains static at less than 15 percent. As we enter the era of targeted therapy, it is critical 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. Amplification and/or gain-of-function alterations in c-KIT (e.g., K642E and L576P) have been identified as the most common oncogenic event in these melanoma subtypes. This has led to clinical evaluation with several c-KIT inhibitors in stratified melanoma patients possessing aberrant c-KIT. Despite an initial response rate in one-quarter of patients treated with c-KIT inhibitors, resistance eventually develops even with dose escalation. Given the high level of genomic alterations frequently identified in these tumors and the lack of specificity of current generation c-KIT inhibitors, it remains unclear if c-KIT is a viable therapeutic target in these melanoma subsets. Moving forward with c-KIT directed therapies requires the development of preclinical models that faithfully mimic the human disease. To this end we have developed a novel melanoma mouse model that enables us to address a role for c-KIT in promoting melanoma initiation, maintenance, and progression in vivo. Expression of mutant c- KIT (L576P) in mouse melanocytes in vivo in the context of Ink4a/Arf loss resulted in the development of melanoma in one-quarter of the mice with a mean latency of 120 days. The goal of the proposed studies is to utilize this flexible melanoma mouse model to evaluate the role of c-KIT in tumor initiation, maintenance and progression and to identify cooperating genetic events to facilitate the development of therapeutic intervention strategies for patients whose tumors possess alterations in c-KIT. We hypothesize that active c-KIT can initiate melanoma and that tumor growth and penetrance will be enhanced in vivo by the addition of cooperating genetic events (e.g., co-expression of HIF1A or MITF). We will test this hypothesis by (Aim 1) assessing the ability of additional c-KIT mutants and potential cooperating genes frequently observed in melanoma to initiate tumors in vivo;
(Aim 2) evaluating a role for c-KIT in tumor maintenance through pharmacological and genetic means;
and (Aim 3) investigating a role for c-KIT in promoting melanoma metastasis in vivo. .
Metastatic melanoma is a devastating disease that is rapidly increasing worldwide. Several factors associated with melanoma initiation and development have recently been identified. Our work will evaluate a role for these elements in melanoma progression in order to develop effective therapeutic intervention strategies.
|Robinson, James P; Rebecca, Vito W; Kircher, David A et al. (2017) Resistance mechanisms to genetic suppression of mutant NRAS in melanoma. Melanoma Res 27:545-557|