Abstract IA006: Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multi- Selective Inhibitors in NRAS-Mutated Melanoma

Abstract Most patients with advanced BRAF or NRAS-driven melanoma receive front-line immunotherapy. However, if immunotherapy fails, BRAF-mutated patients have effective second-line therapies, whereas NRAS-mutated patients lack pathway-targeted options. Recently, RAS (ON) multi-selective inhibitors like RMC-7977, and the investigational agent daraxonrasib, were described that, in partnership with cyclophilin-A (CYPA), inhibit RASGTP signaling. Both compounds demonstrate potent anti- proliferative activity against NRAS-mutated melanoma cell lines and robust anti-tumor activity against preclinical melanoma models. However, in preclinical models, resistance to RMC-7977 monotherapy arose through mutations in Ppia (encoding CYPA) or Map2k1 (encoding MEK1). Moreover, two clinical case studies in patients with NRAS-mutated melanoma treated with daraxonrasib demonstrated clear anti-tumor activity in one patient, but progressive disease in another with co-occurring NRAS and MAP2K1 mutations at baseline. These findings support the potential for daraxonrasib in treatment of patients with NRAS-mutated melanoma, and reveal candidate mechanisms of monotherapy resistance, underscoring the need for combination therapies to improve outcomes. Citation Format: Mona Foth, Wontak Kim, Kayla O'Toole, Brandon Murphy, Montserrat Justo-Garrido, Sanjana Boggaram, Phaedra Ghazi, Euan Brennan, Isaac Wright, Tate Shepherd, Emilio Cortes-Sanchez, Yingyun Wang, Jennifer Roth, Matthew Rees, Melissa Ronan, Jingjing Jiang, Ursula Wasko, Amanda Jiang, Carly Becker, Dekker Deacon, Siwen Hu-Lieskovan, Conan Kinsey, Jeffery Russell, Aparna Hegde, Ignacio Garrido-Laguna, Matthew Holderfield, Mallika Singh, Martin McMahon. Genetic Drivers of Sensitivity or Resistance to RAS (ON) Multi- Selective Inhibitors in NRAS-Mutated 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 IA006.