Mona Foth, Wontak Kim, Kayla O'Toole, Brandon Murphy, Montserrat Justo-Garrido, Sanjana Boggaram, Phaedra Ghazi, Euan Brennan, M. Isaac Wright, Tate Shepherd, Emilio Cortes-Sanchez, Yingyun Wang, Jennifer A. Roth, Matthew G. Rees, Melissa M. Ronan, Jingjing Jiang, Urszula N. Wasko, Amanda Jiang, Carly Becker, Dekker C. Deacon, Sheri L. Holmen, Matthew W. VanBrocklin, Siwen Hu‐Lieskovan, Conan G. Kinsey, Jeffery S. Russell, Aparna Hegde, Ignacio Garrido-Laguna, Matthew Holderfield, Mallika Singh, Martin McMahon
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 inhibit RAS[GTP] signaling in partnership with cyclophilin A (CYPA). Here, we found that both compounds demonstrated 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.