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Abstract 2381: Loss of S6K2 perturbs redox balance and fatty acid metabolism, leading to oxidative cell death

Oncogenes often upregulate nutrient sensing and utilizing pathways, leading to altered metabolism in tumor cells. RAS-driven tumors typify cancers undergoing marked metabolic reprogramming. In melanoma, RAS signaling is often deregulated; while activating mutations in NRAS are present in >25% of tumors, RAS-driven tumors account for almost 50% of cases. However, there are no effective therapies for this type of tumors. Although oncogenic NRAS activates the MAPK pathway, inhibition of this pathway alone has limited antitumor efficacy and most NRAS-mutant tumors are resistant to MAPK inhibitor (MAPKi) monotherapy. We discovered that NRAS-mutant melanomas resistant to MAPKi are highly dependent on the ribosomal protein S6 kinase 2 (S6K2). We demonstrate that loss of S6K2, a signaling effector of the mTORC1 nutrient-sensing pathway, triggers cell death selectively in NRAS-mutant melanoma resistant to MAPKi. Acute depletion of S6K2 enhanced ROS production, lipid synthesis and accumulation of intracellular unsaturated fatty acids. ROS susceptible (poly)-unsaturated fatty acids sensitized cells to ROS, resulting in lipid peroxidation and oxidative cell death. We further determined that S6K2 depletion was coupled to increased expression of markers of apoptosis and ferroptosis, suggesting that S6K2 blockade could trigger multiple forms of cell death, including apoptotic and a ferroptotic-like cell death. Notably, co-inhibition of S6K1 (a S6K isoform that is co-regulated by mTORC1) together with S6K2 diminished the effects of S6K2 blockade, suggesting that selective inhibition of S6K2 is required to induce cell death. Indeed, while silencing of S6K2 triggered lipid peroxidation and oxidative cell death and S6K1 silencing had negligible effects, concomitant depletion of S6K1 and S6K2 attenuated lipid peroxidation and cell death. Mimicking the effects of S6K2 loss by combining an ROS-inducing agent with unsaturated fatty acids or treating tumor cells with lipid peroxidation inducers restrained NRAS-mutant melanoma growth in vitro and in vivo. Taken together, our studies have identified a critical vulnerability of NRAS-mutant melanoma by uncoupling S6K1 and S6K2 to trigger metabolic dysfunction and tumor cell death. This strategy is remarkably distinct from using PI3K/mTOR inhibitors, which concurrently suppress S6K1 and S6K2 and are often cytostatic. We propose that this paradigm could be exploited to develop therapeutic approaches targeting NRAS-mutant tumors and overcome resistance to MAPKi in the context of oncogenic NRAS. Citation Format: Hsin-Yi Chen, Minu Samanta, Patricia Reyes-Uribe, Andrew V. Kossenkov, Xiangfan Yin, Yiling Lu, Mark Axelrod, Michael J. Weber, Qin Liu, Gordon B. Mills, Jessie Villanueva. Loss of S6K2 perturbs redox balance and fatty acid metabolism, leading to oxidative cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2381.