Preprint Watch 2026-05-25: 2 Clinical Failures Flagged for CDK6 | Claidex

Q: Why was this CDK6 preprint flagged?

2 prior Claidex failure claims matched the target-disease mechanism. This bioRxiv preprint reports that DRP1 reactivation contributes to MEK-inhibitor resistance in pancreatic ductal adenocarcinoma cell lines, with CDK6 cited in the abstract as part of the downstream signaling context. The Claidex graph indexes 2 CDK6 failure entry for the abemaciclib AIM trial in HPV-negative HNSCC (slug abemaciclib-cdk46-hnscc-window-aim-soc-shift) and the lerociclib EQRx shutdown in breast cancer (slug lerociclib-cdk46-eqrx-shutdown-hr-breast-cancer). The preprint does not propose a head-to-head test of CDK4/6 inhibition in pancreatic cancer and so does not directly contradict the HNSCC sponsor-decision outcome, but it underscores that CDK6 has limited efficacy when used as monotherapy outside hormone receptor-positive disease. Aligns with the documented failure pattern.

Q: Which clinical failure claims match CDK6 in Pancreatic ductal adenocarcinoma (PDAC), KRAS-driven?

Abemaciclib in HPV-negative HNSCC AIM window trial halted after standard-of-care shift to neoadjuvant immunotherapy (NCT04169074); Lerociclib in HR+/HER2- advanced breast cancer: a clean strategic shutdown in a saturated class (NCT05085002)

Claidex Preprint Watch

doi:10.64898/2026.05.20.726663

Preprint WatchModerateMay 25th, 2026

Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells

Sharmin, S.; Kashatus, J. A.; Adair, S. J.; Bakall Loewgren, E.; Fallahi-Sichani, M.; Bauer, T. W.; Kashatus, D.

DRP1 reactivation contributes to MEK inhibitor resistance in pancreatic cancer cells; CDK6 cited in downstream signaling context.

Moderate contradiction

2 prior failures

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

This bioRxiv preprint reports that DRP1 reactivation contributes to MEK-inhibitor resistance in pancreatic ductal adenocarcinoma cell lines, with CDK6 cited in the abstract as part of the downstream signaling context. The Claidex graph indexes 2 CDK6 failure entry for the abemaciclib AIM trial in HPV-negative HNSCC (slug abemaciclib-cdk46-hnscc-window-aim-soc-shift) and the lerociclib EQRx shutdown in breast cancer (slug lerociclib-cdk46-eqrx-shutdown-hr-breast-cancer). The preprint does not propose a head-to-head test of CDK4/6 inhibition in pancreatic cancer and so does not directly contradict the HNSCC sponsor-decision outcome, but it underscores that CDK6 has limited efficacy when used as monotherapy outside hormone receptor-positive disease. Aligns with the documented failure pattern.

Abstract excerpt

BackgroundIn RAS-mutant tumors, ERK phosphorylates the mitochondrial fission GTPase DRP1 to promote mitochondrial fission. DRP1 activity is tumor-promoting in pancreatic and other RAS-driven cancers, but its role in therapeutic resistance is unknown. MethodsWe developed a panel of patient-derived pancreatic cancer cell lines resistant to the MEK inhibitor trametinib. We used immunofluorescence imaging, in vitro growth assays and orthotopic xenografts to determine the role of DRP1 in trametinib resistance. ResultsWe find that trametinib-resistant cells exhibit increased expression and phosphorylation of DRP1 compared to sensitive counterparts. Quantitative analysis of mitochondrial structure reveals that mitochondria in resistant cells are morphologically distinct and relatively smaller than sensitive cells treated with trametinib. Genetic and pharmacological inhibition of both c-Myc and CDK6 are sufficient to block DRP1 phosphorylation in resistant cells, suggesting that activation of a c-Myc-CDK6 signaling axis drives reactivation of mitochondrial fission in the absence of MAPK signaling. Importantly, deletion of DRP1 leads to either growth inhibition or re-sensitization to trametinib in resistant lines. ConclusionThese findings suggest DRP1 contributes to drug resistance, and that inhibition of mitochondrial fission might be a promising therapeutic strategy to combat resistance to MAPK and RAS inhibitors.

Matching Claidex post-mortems

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.