Abstract LB-090: Molecular and pharmacological characterization of mutant NRAS dependency in melanoma cell lines

Abstract

Abstract Oncogenic NRAS mutations are found in 20 percent of sporadic melanoma cases. Mutant NRAS activates the RAF/MEK/ERK mitogen-activated protein kinase (MAPK), PI3K/AKT and RAC1/PAK kinase signaling pathways, which cooperate to drive melanomagenesis. The complexity of the NRAS signaling network presents a challenge to develop effective therapeutics for NRAS mutant melanoma. Many inhibitors of NRAS-regulated signaling pathways, such as BRAF and MEK/ERK inhibitors are ineffective in this setting. Furthermore, direct NRAS inhibition is pharmacologically challenging. It is likely that combined inhibition of two or more nodes in the NRAS signaling network will be effective in treating NRASmutant melanoma. We have used whole-genome transcriptional profiling coupled with phenotypic characterization of NRAS dependency to derive an NRAS dependency gene expression signature. The signature reveals two key features: (1) NRAS dependency is associated with an kinase-regulated inflammatory gene expression program and (2) expression of the melanocyte lineage factor MITF is strongly associated with NRAS-independent cell proliferation. Based on this knowledge, we have identified combinatorial therapeutic modalities to target either NRAS-dependent or NRAS-independent melanoma subtypes. NRAS-dependent melanoma cell lines undergo apoptotic cell death upon combined inhibition of PAK kinases and Bcl2/Bcl-XL proteins. Conversely, NRAS-independent cell lines are sensitive to the apoptotic effects of combined CDK2 and ERK kinase inhibition. Notably, CDK2 is an MITF transcriptional target gene that mediates a feed-forward loop to potentiate MITF activation. Taken together, our studies highlight phenotypic variations in NRAS mutant melanomas that can be exploited to identify subtype-specific therapeutic targets for NRAS mutant melanoma. Citation Format: Anita K. Mehta, Kevin Hua, Jayant Gadrey, Angelina Fuller, Anurag Singh. Molecular and pharmacological characterization of mutant NRAS dependency in melanoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-090.