Cutaneous melanoma is the most lethal type of skin cancer, with ~76,380 newly diagnosed melanoma and ~10,130 melanoma-associated deaths per year in the US. Thus, there is a need for improved understanding of the molecular pathogenesis and more effective targeted therapies for this devastating disease. The recent work of The Cancer Genome Atlas Network has defined melanoma as an RTK/RAS-driven solid tumor that can be classified into four genomic subtypes: BRAF-mutant, RAS-mutant, NF1-mutant, and triple-wild-type. This landmark study highlighted the important role of the previously understudied NF1 tumor suppressor in melanoma pathogenesis, especially for the 9% of melanoma patients who have acquired inactivating NF1-mutations, but lack hotspot mutations that activate BRAF or RAS. To date, animal models have not been developed for the NF1-mutant subtype of melanoma, which has significantly impaired the development of novel therapeutic strategies for this subtype. Here we report the first zebrafish model for NF1-mutant melanoma, which we generated by combining the loss of nf1 with loss of both pten and p53. The resultant compound mutant zebrafish develop aggressive melanomas from the age of 7 weeks and the tumor penetrance is 80% by the age of 18 weeks. We demonstrate further that these high-risk zebrafish melanomas were exclusive of hotspot mutations of braf and nras. Sustained inhibition of both MEK and PI3K suppressed tumor progression in vivo, whereas inhibition of MEK or PI3K alone was insufficient to suppress the growth of these tumors. Surprisingly, single agent therapy with rapamycin, an MTOR inhibitor, proved even better for short- and long-term suppression of tumor cell growth in nf1/pten-mutant melanomas. Thus our model appears ideal for the testing of drugs that will prove uniquely active for the significant subset of NF1-mutant, BRAF/NRAS-wildtype human melanomas.

Citation Format: Shuning He, Marc R. Mansour, Hillary M. Layden, Scott J. Rodig, E. Elizabeth Patton, A. Thomas Look. A zebrafish model of NF1-mutant melanomas that lack activating mutations of BRAF or NRAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 801. doi:10.1158/1538-7445.AM2017-801