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Preprint WatchModerateSeptember 19th, 2026

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.

Genetic and pharmacological ERK5 inhibition induced selective CDK6 proteasomal degradation without affecting CDK4, and co-treatment with the ERK5 inhibitor JWG-071 and palbociclib synergistically reduced viability and increased apoptosis in melanoma and serous endometrial cancer cells.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The mechanistic content here is a selective route to CDK6 protein loss through ERK5 inhibition, proposed as a way to deepen palbociclib response outside the approved breast cancer setting. Two CDK6 programmes sit in the Claidex record, and neither was stopped on biology. Lerociclib in HR-positive HER2-negative advanced breast cancer (lerociclib-cdk46-eqrx-shutdown-hr-breast-cancer) ended when the sponsor shut down, and abemaciclib in HPV-negative head and neck squamous cell carcinoma (abemaciclib-cdk46-hnscc-window-aim-soc-shift) ended on strategic reprioritization after the standard of care moved. That pattern means CDK4/6 inhibition in new indications keeps failing to reach a readout rather than failing at one, so a combination strategy that depends on a second novel agent inherits two portfolio risks instead of one. The preclinical synergy is in cell lines only, and the claim that ERK5 inhibition improves palbociclib efficacy has not been tested in any animal or human setting reported in this preprint.

Abstract excerpt

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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2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.