Abstract 236: Selective inhibition of NRAS-GTP in cancer models with small molecule NEOS-223

Abstract NRAS is one of the second most mutated RAS oncogene followed by KRAS in cancer, and efforts to target directly inhibit its function have been continuing for years. Strategies targeting oncogenic RAS pathway include direct and indirect approaches. However, despite aggressive efforts in recent years, there are no clinical or on the market that directly target NRAS and inhibit its aberrant function in various cancers. The recent success of KRAS G12C inhibitors has demonstrated clinical efficacy in patients and approved for the treatment of non-small cell lung cancer. Despite the promising success of targeting KRAS, there remains no available inhibitor that targets NRAS alone. In pursuit of NRAS inhibition and we have developed a small molecule potent selective non-covalent inhibitor that inhibits NRAS-GTPase activity of both mutant and wild type of NRAS while sparing KRAS and HRAS. Our molecular dynamics simulation studies reveal the structural basis of inhibitor binding at the switch II pocket in NRAS. NEOS-223 demonstrated potent activity against cancer models with NRAS Q61K and inhibited cancer growth. Treatment with NEOS-223 led to tumor growth blockage and well tolerated in diverse RAS-addicted preclinical cancer models. NEOS-223 has a greater synergistic effect on inhibition of cell proliferation combined with specific targeted inhibitors such as gefitinib (EGFR), sotorasib (KRAS G12C), vemurafenib (BRAF V600E) and MRTX1133 (KRAS G12D) correlating with stronger suppression of EGFR-RAS-MAPK signaling. Resistance to KRAS inhibitors (G12C, G12D) seemed to be driven by EGFR mediated upregulation of wild type RAS activity. Feedback reactivation of adaptive RAS family members including NRAS (WT) occurs following KRAS inhibition, a key mediator of resistance. Co-targeting with NEOS-223 abrogates the EGFR-mediated feedback NRAS reactivation enhancing the antitumor effects improving the efficacy in KRAS mutant tumors with KRAS inhibition and similar effects were also observed in BRAF mutant colon cancer with inhibition of NRAS with NEOS-223 plus vemurafenib. Our study highlights the feasibility of developing NRAS selective inhibitor for therapeutic efforts and these results suggest that NRAS plus KRAS to be a promising strategy for treating both EGFR and RAS mutant tumors. Overall, these data provide important mechanistic insight to guide therapeutic strategies targeting NRAS mutant, dependent and resistance tumors. Citation Format: Harish Potu, 1Sara A. Little, 1Stephanie Fedorchak, 1Sumathi Chittamuru, 1Timothy M. Murphy, 1Sarah Di Croce, 1Melanie George, 1Jeremy Harvey, 2Neil Rory McFarlane, 2Piet Christiaens, 3Timothy Fisher, 1Laxman S. Desai1. Selective inhibition of NRAS-GTP in cancer models with small molecule NEOS-223 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 236.