Abstract 900: In vivo modeling of NRAS-mutant melanoma reveals differential preventative efficacy amongst SPF30 sunscreens

Abstract

Abstract Cutaneous melanoma claims the life of one American every hour, and while the etiology of this tumor type is not entirely understood, exposure to ultraviolet (UV) radiation (280-340nm) is a major risk factor. For this reason, the use of UV-blocking sunscreens is strongly advocated; however, few studies have tested the relative efficacy of these agents in preventing melanoma formation in vivo. Here, we employed a new genetically engineered mouse model (TpN61R) to examine the ability of 6 chemically distinct SPF30 sunscreens to prevent melanoma. In this TpN61R model, topical 4-hydroxytamoxifen (4OHT) treatment induces the melanocyte-specific expression of oncogenic NRas as well as inactivation of the p16INK4a tumor suppressor. These genetic lesions co-occur in ∼24% of all human melanomas, making the TpN61R model biologically relevant. Since NRAS mutations are an early and UV-independent event in human melanoma, TpN61R mice were first painted with 4OHT and then exposed to a single dose of 4.5 kJ/m2 UVB light one day later. Exposed skin from TpN61R mice showed transient cyclobutane pyrimidine dimer (CPD) formation, however no evidence of edema or inflammation was observed. Despite these mild effects, UVB exposure reduced the melanoma-free survival of TpN61R mice by 80% and increased tumor incidence rate from 1.2 to 3.4 tumors/mouse. Further experiments using a variety of UVB doses (0.25, 1.0, 2.3 and 9.0 kJ/m2) in the TpN61R model revealed a dose-dependent increase in early melanoma incidence. Together, these data establish the exquisite cooperation of UV light and oncogenic NRas mutations in driving melanoma. Taking advantage of this unique model, we tested the preventative efficacy of SPF30 sunscreens with differing chemical composition. Sunscreens components included UVA (avobenzene), UVB (homosalate, octisalate) and broad spectrum (oxybenzone, octocrylene, zinc oxide) blocking agents. Application of sunscreen prior to UVB exposure decreased DNA damage, delayed melanoma onset and reduced tumor incidence in a sunscreen-dependent manner. Thus, SPF30 sunscreens do not equally prevent UVB-induced, NRAS mutant melanoma. This work establishes the first in vivo system to test sunscreen efficacy in NRAS-driven melanoma and will help direct the development of improved melanoma preventatives. Citation Format: Andrea M. Holderbaum, Rebecca C. Hennessey, James E. Gillahan, Anamaria Bonilla, Conor Delaney, Raleigh D. Kladney, Kathleen L. Tober, Tatiana M. Oberyszyn, Christin E. Burd. In vivo modeling of NRAS-mutant melanoma reveals differential preventative efficacy amongst SPF30 sunscreens. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 900.