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.