Data from Genetic Drivers of Sensitivity or Resistance to RAS(ON) Multiselective Inhibitors in <i>NRAS</i>-Mutated Melanoma

<jats:p>&lt;div&gt;Abstract &lt;p&gt;Most patients with advanced BRAF- or NRAS-driven melanoma receive first-line immunotherapy. However, if immunotherapy fails, &lt;i&gt;BRAF&lt;/i&gt;-mutated patients receive effective second-line therapies, whereas &lt;i&gt;NRAS&lt;/i&gt;-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 &lt;i&gt;NRAS&lt;/i&gt;-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 &lt;i&gt;Ppia&lt;/i&gt; (encoding CYPA) or &lt;i&gt;Map2k1&lt;/i&gt; (encoding MEK1). Moreover, 2 clinical case studies in patients with &lt;i&gt;NRAS&lt;/i&gt;-mutated melanoma treated with daraxonrasib demonstrated clear antitumor activity in 1 patient but progressive disease in another with co-occurring &lt;i&gt;NRAS&lt;/i&gt; and &lt;i&gt;MAP2K1&lt;/i&gt; mutations at baseline. These findings support the potential for daraxonrasib in the treatment of patients with &lt;i&gt;NRAS&lt;/i&gt;-mutated melanoma and reveal candidate mechanisms of monotherapy resistance, underscoring the need for combination therapies to improve outcomes.&lt;/p&gt; Significance:&lt;p&gt;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.&lt;/p&gt;&lt;/div&gt;</jats:p>