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<p>Despite the advent of immune-oncological therapies, patients with advanced <i>NRAS</i>-mutant melanoma still have a significantly worse prognosis than their <i>BRAF</i>-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 <i>NRAS</i>-mutant melanoma. Accordingly, MAPKi/ERK5i co-inhibition was capable of triggering a sustained cell cycle arrest in <i>NRAS</i>-mutant melanoma cells, but the key mediator(s) of its vigorous anti-proliferative effect remain elusive. Here, we further investigated the mechanism of MAPKi/ERK5i-induced cell cycle arrest in <i>NRAS</i>-mutant melanoma cells using both genetic methods and pharmacological inhibitors. Transcriptome analysis of human <i>NRAS</i>-mutant melanoma cells established that MAPKi/ERK5iinduced a near-complete shutdown of the mitotic machinery as consequence of a sustained G1 cell cycle arrest. This arrest was not only observed in diverse treatment-naïve melanoma cells but could also be induced in cells that already had developed resistance to therapeutic MEK inhibition (MEKi) and was accompanied by suppression of Cyclin D1 and E2F-mediated gene expression. Forced expression of Cyclin D1 and its effector kinase CDK4 restored cell cycle progression and mitotic gene expression in <i>NRAS-</i>mutant melanoma cells exposed to MEKi/ERK5i, implying Cyclin D/CDK4 activity as major target of combined MEKi/ERK5i. These findings suggest Cyclin D/CDK4 dependency as a major vulnerability of <i>NRAS</i>-mutant melanoma that could effectively be targeted by combined MAPKi/ERK5i.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月6日

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  • Rupesh Paudel,
  • Simon Goller,
  • Felix Deutzmann,
  • Alina Gillitzer,
  • Katharina Meder,
  • Andrea Knorz,
  • David Schrama,
  • Matthias Goebeler,
  • Marc Schmidt

摘要

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/ERK5i-induced cell cycle arrest in NRAS-mutant melanoma cells using both genetic methods and pharmacological inhibitors. Transcriptome analysis of human NRAS-mutant melanoma cells established that MAPKi/ERK5iinduced a near-complete shutdown of the mitotic machinery as consequence of a sustained G1 cell cycle arrest. This arrest was not only observed in diverse treatment-naïve melanoma cells but could also be induced in cells that already had developed resistance to therapeutic MEK inhibition (MEKi) and was accompanied by suppression of Cyclin D1 and E2F-mediated gene expression. Forced expression of Cyclin D1 and its effector kinase CDK4 restored cell cycle progression and mitotic gene expression in NRAS-mutant melanoma cells exposed to MEKi/ERK5i, implying Cyclin D/CDK4 activity as major target of combined MEKi/ERK5i. These findings suggest Cyclin D/CDK4 dependency as a major vulnerability of NRAS-mutant melanoma that could effectively be targeted by combined MAPKi/ERK5i.