Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation

Summary

Histone H3K36 trimethylation (H3K36me3) is frequently lost in multiple cancer types, identifying it as an important therapeutic target. Here we identify a synthetic lethal interaction in which H3K36me3-deficient cancers are acutely sensitive to WEE1 inhibition. We show that RRM2, a ribonucleotide reductase subunit, is the target of this synthetic lethal interaction. RRM2 is regulated by two pathways here: first, H3K36me3 facilitates RRM2 expression through transcription initiation factor recruitment; second, WEE1 inhibition degrades RRM2 through untimely CDK activation. Therefore, WEE1 inhibition in H3K36me3-deficient cells results in RRM2 reduction, critical dNTP depletion, S-phase arrest, and apoptosis. Accordingly, this synthetic lethality is suppressed by increasing RRM2 expression or inhibiting RRM2 degradation. Finally, we demonstrate that WEE1 inhibitor AZD1775 regresses H3K36me3-deficient tumor xenografts.

Graphical Abstract

Highlights

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  WEE1 inhibition selectively kills H3K36me3-deficient cancer cells

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  These cells are killed through dNTP starvation because of RRM2 depletion

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  RRM2 is regulated by H3K36me3 through transcription and WEE1 via degradation

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  WEE1 inhibitor AZD1775 regresses H3K36me3-deficient tumors in vivo

Abstract

Pfister et al. show that WEE1 inhibition selectively kills H3K36me3-deficient cancer cells through dNTP starvation resulting from RRM2 depletion. Pfister et al. further show that H3K36me3 facilitates RRM2 transcription whereas WEE1 inhibition promotes RRM2 degradation via CDK activation.