MEK5/ERK5 inhibition sensitizes NRAS-mutant melanoma to MAPK-targeted therapy by preventing Cyclin D/CDK4-mediated G1/S progression.

ABSTRACT: Despite the advent of immune-oncological therapies, patients with advanced NRAS-mutant melanoma still have a significantly worse prognosis than their BRAF-mutant counterparts. This is mainly due to a high propensity for resistance to available therapies targeting the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway (MAPKi). Preclinical studies and mouse models have implicated the stress-activated MEK5/ERK5 MAPK cascade as a major resistance pathway activated by MAPKi-based targeted therapy in NRAS-mutant melanoma. Accordingly, MAPKi/ERK5i co-inhibition was capable of triggering a sustained cell cycle arrest in NRAS-mutant melanoma cells, but the key mediator(s) of its vigorous anti-proliferative effect remain elusive. Here, we further investigated the mechanism of MAPKi/ERK5

SUBMITTER: Paudel R 

PROVIDER: S-EPMC12501213 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature