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Preprint WatchMildOctober 10th, 2026

A mitotic restriction point for extrachromosomal DNA hubs in cancer cells

Yan, X.; Wong, I. T.-L.; Hassan, M. M.; Li, R.; Kraft, K.; Gnanasekar, A.; Mischel, P. S.; Chang, H. Y.

WEE1 regulates extrachromosomal DNA hub integrity and oncogene expression, with CDK1 and CDK2 programmes carrying unresolved damage into mitosis to reorganise ecDNA on mitotic chromosomes

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

This preprint identifies WEE1 in an optical screen as a regulator of extrachromosomal DNA hub integrity and oncogene expression, with CDK1- and CDK2-regulated programmes cooperating to carry unresolved damage into mitosis and reorganise ecDNA tethered to mitotic chromosomes. Claidex holds one WEE1 failure, azenosertib-wee1-zap-it-tnbc-safety-termination, which ended on a safety signal rather than on absence of activity. The preprint proposes a selection principle the clinical failure never had the chance to test, namely that ecDNA-positive tumours would be the population in which WEE1 inhibition produces the largest transcriptional effect. Any revival of WEE1 inhibition should pair an ecDNA-status biomarker with a dosing schedule designed around the toxicity that stopped the previous program.

Abstract excerpt

Extrachromosomal DNA (ecDNA) is widespread in human cancers and promotes tumour evolution, intratumour heterogeneity and poor clinical outcomes. ecDNA molecules tend to cluster into micron-scale nuclear hubs that enhance oncogene transcription. However, how these higher-order assemblies form and persist remains largely unknown. Here we discover mitosis as the critical window for ecDNA hub organisation across cell generations. We develop an optical screen that identifies the mitotic-entry regulator WEE1 as an important regulator of hub integrity and oncogene expression. Analysis of WEE1 perturbation reveals that CDK1- and CDK2-regulated programmes cooperate to carry unresolved damage into mitosis, promoting reorganisation of ecDNA tethered to mitotic chromosomes. Long-term live-cell imaging shows that, in unperturbed cells, ecDNA hub architecture is remodelled primarily during mitosis and subsequently maintained throughout interphase. This coupling between mitotic and interphase organisation is conserved across diverse cancer types and ecDNA-associated oncogenes. Together, these findings define a mitotic restriction point that governs ecDNA hub organisation, oncogene expression and ecDNA inheritance through successive cell generations, revealing a potential window for therapeutic intervention in ecDNA-driven cancers.

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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.