S6K2 IS A NOVEL TARGET IN MAPKi-RESISTANT NRAS-MUTANT MELANOMA

Melanoma is often driven by NRAS mutations. Although oncogenic NRAS activates MAPK signaling, inhibition of this pathway has limited efficacy in NRAS-mutant tumors. As there are limited options to treat these tumors, there is a pressing need to identify NRAS-mutant-specific vulnerabilities that can be therapeutically exploited. Metabolic reprogramming is one of the hallmarks of RAS-mutant tumors, creating a dependency on key metabolic pathways. This dependency could be leveraged to combat these tumors. We discovered that abrogation of S6K2, a mTORC1 effector, triggers accumulation of unsaturated fatty acids, lipid peroxidation and cell death selectively in NRAS-mutant melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induced upregulation of S6K1 and PPAR, triggering apoptotic and ferroptosis-like cell death. Conversely, depletion of S6K1 diminished lipid synthesis and cell proliferation, without eliciting cell death. Collectively, our data indicate that a fine balance between S6K1 and S6K2 activity and metabolic homeostasis is required to prompt cell death of NRAS-mutant melanoma. S6K2 is hence a novel therapeutic target for MAPKi-resistant NRAS-mutant melanoma. RNA-seq for WT, and knockdown of S6K1 and S6K2