Abstract
Metastatic melanoma, the most aggressive form of skin cancer, accounts for the majority of skin cancer-related deaths. While targeted kinase inhibitors have improved outcomes for patients with BRAF-mutated melanomas, their efficacy is often short-lived, and effective treatments for other mutations, such as NRAS, remain scarce. To address this clinical need, we investigated the combination of the novel panRAF inhibitor, brimarafenib, and the MEK inhibitor, mirdametinib, both of which target the MAPK pathway downstream of NRAS. This study demonstrates the efficacy of this combination in NRAS-mutated melanoma and is currently also investigated in a phase I/IIa clinical study. In vitro, the brimarafenib and mirdametinib combination exhibited synergistic effects, significantly inhibiting the growth of patient-derived NRAS-mutated melanoma cell lines. A colony formation assay showed that this combination prevented the emergence of drug-resistant clones, suggesting a strong potential to reduce disease relapse. Transcriptional and proteomic analyses revealed that the observed growth inhibition was due to modulation of MAPK signaling and induction of apoptosis. In vivo studies further validated these findings, showing that the combination treatment inhibited tumor growth and significantly prolonged survival in mouse models bearing patient-derived NRAS-mutated melanoma tumors. Given the tolerability of this combination in vivo, our results suggest that brimarafenib and mirdametinib represent a promising therapeutic strategy for patients with NRAS-mutated melanomas and potentially other RAS-mutated solid tumors.