Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multiselective Inhibitors in NRAS-Mutated Melanoma.

Most patients with advanced BRAF- or NRAS-driven melanoma receive first-line immunotherapy. However, if immunotherapy fails, BRAF-mutated patients receive effective second-line therapies, whereas NRAS-mutated patients lack pathway-targeted options. Recently, RAS(ON) multiselective inhibitors like RMC-7977 and the investigational agent daraxonrasib were described that inhibit RAS[GTP] signaling in partnership with cyclophilin A (CYPA). In this study, we found that both compounds demonstrated potent antiproliferative activity against NRAS-mutated melanoma cell lines and robust antitumor 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, 2 clinical case studies in patients with NRAS-mutated melanoma treated with daraxonrasib demonstrated clear antitumor activity in 1 patient but progressive disease in another with co-occurring NRAS and MAP2K1 mutations at baseline. These findings support the potential for daraxonrasib in the treatment of patients with NRAS-mutated melanoma and reveal candidate mechanisms of monotherapy resistance, underscoring the need for combination therapies to improve outcomes. SIGNIFICANCE: Inhibition of RAS signaling with RMC-7977 or daraxonrasib displays potent activity in models of NRAS-driven melanoma, with drug resistance mediated by mutational silencing of CYPA expression or activation of MEK1.