Abstract NRAS mutations drive 20–30% of melanomas through sustained MAPK and PI3K signaling, but therapeutic strategies for NRAS-mutant patients remain a significant therapeutic challenge. Patients with NRAS-mutant (NRASMut) melanoma are treated with immune checkpoint inhibitors (ICi) as first line treatment. However, not all patients respond, and some develop resistance and relapse. There are currently no second-line treatments available for NRASMut melanoma patients who progress on ICi. Therefore, effective strategies for NRASMutmelanoma refractory to current treatments are sorely needed. Although pan-RAS inhibitors offer new promise, we have found that only a subset of NRASMut melanomas are sensitive to pan-RASi monotherapy. Furthermore, MAPK pathway inhibitors (MAPKi) as single agents have shown limited responses and failed to improve patient’s survival, highlighting a need for effective combination therapies. We discovered that the ribosomal protein S6 kinase β-2 (S6K2), a convergent subnetwork downstream from the MAPK and PI3K pathways, is a critical vulnerability in NRASMut melanoma resistant to MAPKi (MAPKi-R). We demonstrate that selective S6K2 blockade, but not S6K1 inhibition, perturbs lipid metabolism, enhances fatty acid unsaturation, and triggers lethal lipid peroxidation in MAPKi-R NRASMut melanoma. Genetic or pharmacological S6K2 inhibition induces endoplasmic reticulum stress and PPARα activation, triggering cell death selectively in MAPKi-R melanoma. Our first-generation S6K2i, shows anti-melanoma activity and restrains the growth of MAPKi-R tumors, further providing proof of principle that S6K2 is a critical vulnerability for NRASMUT MAPKi-R melanoma. Moreover, we discovered that inhibition of S6K2 sensitizes MAPKi-R melanoma to MAPKi (such as the pan-RAS inhibitor RMC-6236). We have also defined the mechanism through which RASi potentiates the activity of our novel S6K2i. Taken together our studies demonstrate the therapeutic value of inhibiting S6K2 and that targeting this critical subnetwork downstream of PI3K is a viable approach to offset RASi/MAPKi resistance in NRASMut melanoma and possibly other RAS-driven tumors. Citation Format: Brittany Lipchick, Segundo W. Del Aguila, Yulissa A. Tirado, Romina Garavito-Salini, Zhiyuan Zhang, John Pezzullo, Adam Guterres, Qin Liu, Jeffrey D. Winkler, Ronen Marmorstein, Jessie Villanueva. Targeting S6K2 overcomes resistance to RAS inhibition in NRAS-mutant melanoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr PR001.
Lipchick et al. (Thu,) studied this question.