Suppression of NRAS-mutant melanoma growth with NRAS-targeting Antisense Oligonucleotide treatment reveals therapeutically relevant kinase co-dependencies.

BACKGROUND: Melanoma is an aggressive form of skin cancer, and patients with NRAS-mutant melanoma face limited treatment options due to the lack of direct NRAS inhibitors. This study explores the utilization of antisense oligonucleotides (ASOs) to directly target NRAS-mRNA for therapeutic approaches. METHODS: We designed and tested NRAS-mRNA-targeting ASOs. Experiments in melanoma cell lines and mouse models assessed effects on cell survival, apoptosis, and tumor growth. A kinase activity profiling platform identified therapeutically exploitable pathways influenced by NRAS suppression. RESULTS: Our research suggests that ASOs do not need to target the mutated NRAS segment to be effective. ASOs designed for the non-mutated NRAS sequence eliminate NRAS-dependent melanoma cells while sparing NRAS wild-type cells. They act independently of subcellular target localization, reduce NRAS-mRNA levels, inhibit MAPK signaling, induce apoptosis, and suppress melanoma growth in vitro and in vivo. Outcomes of high-throughput kinase activity mapping (HT-KAM) indicate a significant dependency between NRAS-mRNA expression and the activity of MEK1, FGFR2, and CDK4 kinases. Co-targeting these kinases enhances the antiproliferative effect of NRAS ASOs, showing synergy. CONCLUSIONS: These findings highlight antisense oligonucleotides as a promising therapeutic approach for NRAS-mutant melanoma. By effectively blocking NRAS-mRNA, this strategy overcomes challenges posed by the absence of a direct small molecule inhibitor for NRAS, and may offer new treatment options for patients.