ERK5 inhibition triggers CDK6 proteasomal degradation and enhances palbociclib efficacy in cancer cells

Faundez Vidiella, C.; Sfragano, Y.; Tusa, I.; Stecca, B.; Espinosa Gil, S.; Lizcano, J. M.; Rovida, E.

doi:10.64898/2026.09.17.752291

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bioRxiv · 10.64898/2026.09.17.752291

ERK5 inhibition triggers CDK6 proteasomal degradation and enhances palbociclib efficacy in cancer cells

Faundez Vidiella, C.·Sfragano, Y.·Tusa, I.·Stecca, B.·Espinosa Gil, S.·Lizcano, J. M.·Rovida, E.

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Abstract

Advanced endometrial cancer (EC) and melanoma are two malignancies with poor treatment options at advanced stages. CDK4 and CDK6 kinases play a central role in the regulation of cell proliferation by controlling progression through G1/S transition. CDK4/CDK6 inhibitors are currently in clinical trials for advanced ECs, whereas melanoma tumors frequently carry mutations affecting the CDK4/CDK6 pathways that support the therapeutic potential of these kinases. The MAP kinase ERK5 promotes tumor progression by driving cell-cycle progression, yet its functional interplay with CDK4/6-dependent cell cycle control remains poorly defined. Here, we investigated the relationship between ERK5 and CDK4/6 in melanoma and serous EC cells, uncovering the benefits of their co-targeting. Both genetic and pharmacological inhibition of ERK5 induced CDK6 proteasomal degradation, without affecting CDK4 protein levels. Co-treatment with the ERK5 inhibitor JWG-071 and palbociclib synergistically reduced cell viability and increased apoptosis in both melanoma and EC cells, compared with single-agent treatments. Mechanistically, combined inhibition of ERK5 and CDK4/6 reinforced cell-cycle inhibitory signaling through p21 induction and reduced phospho-retinoblastoma levels. These findings suggest that targeting ERK5 may improve the anticancer efficacy of palbociclib, at least in melanoma and serous EC tumors.

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Faundez Vidiella, C., Sfragano, Y., Tusa, I., Stecca, B., Espinosa Gil, S., Lizcano, J. M., Rovida, E.. 2026-09-18. ERK5 inhibition triggers CDK6 proteasomal degradation and enhances palbociclib efficacy in cancer cells. https://doi.org/10.64898/2026.09.17.752291

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