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Preprint WatchMildSeptember 9th, 2026

The Greatwall/PP2A-B55α axis remodels the G2/M boundary and shapes cellular dependence on PKMYT1

Zach, R.; Herbert, A.; Dragoi, C.-M.; Meredith, M.; Gadelkarim, L.; Foster, W.; Hochegger, H.

Positions PP2A-B55 as a context-dependent G2/M repressor that cooperates with PKMYT1 and, to a lesser extent, WEE1, with cancer cells showing marked sensitisation to PKMYT1-selective RP-6306 and only modest sensitisation to WEE1-selective adavosertib.

Mild contradiction

1 prior failure

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

The mechanistic claim here separates WEE1 from PKMYT1 in S and G2 phase control and reports that cancer cells sensitised to Greatwall and PP2A-B55 perturbation respond markedly to PKMYT1 inhibition and only modestly to WEE1 inhibition. The Claidex record carries one WEE1 failure, azenosertib-wee1-zap-it-tnbc-safety-termination, which ended on tolerability rather than on a demonstrated absence of target engagement. Read together, the two point in the same direction for programme design: if the therapeutic window for WEE1 inhibition is narrow on the safety side, and the G2/M dependence in cancer cells runs preferentially through PKMYT1, then the argument for pushing further WEE1 inhibitors through toxicity-limited schedules weakens relative to the adjacent node. This is a MILD flag because the single documented WEE1 failure was a safety termination, not an efficacy readout.

Abstract excerpt

The switch-like G2/M transition and mitotic exit depend on a feedback loop comprising CDK1, Greatwall kinase, and the PP2A-B55 phosphatase. Monogenic disruptions of these regulators impair cellular functions, drive genomic instability, and promote cancer-associated characteristics. Yet how perturbations of this feedback loop interact, and whether their effects depend on cellular context, remain unclear. Here, we assess how combinatorial perturbations of CDK1, Greatwall, and PP2A-B55 affect cell-cycle control in non-transformed RPE-1 and tumour-derived HeLa cells. We identify PP2A-B55 as a context-dependent G2/M repressor with a critical role in cancer cells, where it cooperates with PKMYT1 and, to a lesser extent, WEE1 to prevent premature mitosis. In cancer cells, but not in non-transformed cells, reduced PP2A-B55 activity and Greatwall overexpression produce marked sensitisation to the PKMYT1-selective RP-6306 and modest sensitisation to the WEE1-selective adavosertib. This asymmetric sensitisation reflects a functional separation between WEE1 and PKMYT1 in S- and G2-phase control. Our work outlines fundamental and cell-type-specific contributions of CDK1, Greatwall and PP2A-B55 to cell-cycle regulation and proposes G2/M plasticity as a vulnerability with utility in PKMYT1-targeted therapy.

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1 of 1 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.