Authors: Lorelei Sole, Riley Elmer, Gennie Parkman, David Kircher, Katie Culver, Tursun Turapov, David Viskochil, Sheri Holmen
Mentors: Sheri Holmen
Insitution: University of Utah
Melanoma is the deadliest form of skin cancer, largely due to its potential to metastasize. In the state of Utah, melanoma is the third-most diagnosed cancer, and alarmingly, Utah has the highest incidence per capita of melanoma in the entire United States. Metastatic melanoma often has a poor prognosis, with a five-year survival rate estimated at 32%.
Genetic alterations are major drivers of melanoma, and 91% of melanomas contain mutations that lead to hyperactivated MAPK/AKT pathway signaling. NF1 is the third most commonly dysregulated gene, behind BRAF and RAS, that can hyperactivate MAPK/AKT signaling. NF1 mutations are present in just under 20% of melanomas, and more than half of these are predicted to be loss of function mutations (NF1 LoF). Although previous research has established that NF1 LoF frequently co-occurs with mutations in both the oncogene BRAF and tumor suppressors PTEN and CDKN2A, the cooperation of both NF1 LoF and mutant BRAF in the presence of altered PTEN and CDKN2A remains understudied. To address this, we used an established autochthonous in vivo mouse model of melanoma based on the RCAS/TVA avian retroviral system to assess the ability of loss of NF1 to cooperate with mutant BRAF in the presence of PTEN and CDKN2A loss to promote tumor progression and metastasis. These results demonstrated that mutant BRAF and NF1 LoF cooperate in the context of PTEN and CDKN2A loss to decrease survival from around 140 days (NF1 LoF alone) to 60 days (NF1 LoF and mutant BRAF), and more research will be completed to evaluate this cooperation further. With about 20% of melanomas exhibiting both BRAF and NF1 mutations, this research addresses a pressing clinical need and offers the potential to discover treatment options for a significant patient population.