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This study reveals that in BRAFV600E-mutated melanoma cells, inhibiting either the ERK5 or ERK1/2 signaling pathway causes compensatory activation of the other pathway, allowing cancer cells to survive treatment. The researchers identified R-Ras protein as the key molecular switch coordinating this reciprocal activation, and demonstrated that blocking R-Ras with a pan-Ras inhibitor (RMC-6236) enhances the effectiveness of both ERK5 and BRAF-MEK1/2-ERK1/2 inhibitors in reducing melanoma cell viability and tumor growth in laboratory models.
Why it matters
These findings explain a major mechanism of drug resistance in melanoma patients treated with BRAF and MEK inhibitors, and suggest that combining these therapies with Ras inhibitors could prevent treatment failure. This research provides a rationale for developing combination therapy strategies that may improve outcomes for melanoma patients whose tumors currently develop resistance to standard targeted treatments.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Malignant melanoma is an aggressive cancer driven by aberrant Mitogen Activated Protein Kinase (MAPK) signaling. Although BRAF and MEK1/2 inhibitors improved the outcome in patients with BRAF mutations, resistance frequently arises. Accumulating evidence at the preclinical level has identified the activation of the MEK5/ERK5 pathway among the mechanisms sustaining the growth in different types of cancer upon Ras-RAF-MEK1/2-ERK1/2 pathway inhibition. On the other hand, there is a lack of information concerning the effect of ERK5 inhibition on the RAF-MEK1/2-ERK1/2 pathway in melanoma. Here, we report that both genetic and pharmacological inhibition of ERK5 leads to hyperactivation of the MEK1/2-ERK1/2 cascade in BRAFV600E-mutated melanoma cells. Starting from available transcriptomic data showing that ERK5 knockdown increases the mRNA levels of the Ras-Related Protein R-Ras, we identified R-Ras as a key mediator of ERK1/2 activation upon ERK5 inhibition. Indeed, R-Ras silencing prevented ERK1/2 hyperactivation and potentiated the anti-proliferative and pro-apoptotic effects of ERK5 inhibition. Intriguingly, R-Ras knockdown impaired the increase of ERK5 phosphorylation observed in response to BRAF-MEK1/2-ERK1/2 inhibition and enhanced apoptosis induced by the latter. Constitutively active R-Ras mutant promoted ERK5 phosphorylation/activation, positioning R-Ras upstream of ERK5. Pharmacological inhibition of Ras with the pan-Ras inhibitor RMC-6236 reduced melanoma cell viability and potentiated the tumor suppression activity of either ERK5 or BRAF-MEK1/2-ERK1/2 inhibitors, in both 2D and 3D tumor models. Collectively, our findings identify R-Ras as a critical regulator of the bidirectional crosstalk between ERK1/2 and ERK5 pathways, supporting its potential as a therapeutic target to overcome adaptive resistance in BRAFV600E-mutant melanoma.