Utilizing a Novel Giant Congenital Melanocytic Nevus Murine Model to Investigate Therapeutic Strategies and Model Tumorigenesis

Abstract

Giant congenital melanocytic nevi (gCMN) are oncogene-driven proliferations of melanocytes present since birth that are greater than 20 cm in projected adult size, and have a melanoma conversion frequency of ranging from 5-15%. Patients with gCMN typically develop melanoma in early childhood that is extremely aggressive and almost universally fatal. Therefore, targeted therapies to induce nevus regression would be enormously beneficial. NRAS activating mutations are postulated to be the driver mutation gCMN. Described here are two novel gCMN preclinical murine models that harbor an NrasQ61R mutation. Evaluation of both the constitutive nevus model (Dct promoter-driven constitutive Cre with NrasQ61R mutation) and the inducible nevus model (Tyr promoter-driven tamoxifen-inducible CreERT2 with NrasQ61R mutation) demonstrate that both models recapitulate human gCMN histological architecture and model spontaneous tumorigenesis. Of the various drug candidates tested, topical administration of a combination of the MEK inhibitor binimetinib and the c-KIT inhibitor imatinib was superior in causing almost complete nevus regression, as measured by a reduction of melanin deposition and melanocytes in the dermal layer. This may represent a potential topical treatment strategy for the regression of gCMN that avoids both the more deleterious side effects of either systemic drug administration or large-scale surgical procedures. Ultimately, this preclinical murine model may help generate new information about the rare, but deadly gCMN that may aid in improving daily symptoms from these lesions as well as hopefully reduce overall melanoma risk.