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

• DOI: 10.1016/j.ccell.2015.09.015
• Publication Date: 2015-10-25T10:32:02Z
• Authors: Sophia X. Pfister; Enni Markkanen; Yanyan Jiang; Sovan Sarkar; Mick Woodcock; Giulia Orlando; Ioanna Mavrommati; Chen-Chun Pai; Lykourgos-Panagio...; Neele Drobnitzky; Grigory L. Dianov; Clare Verrill; Valentine M. Maca...; Songmin Ying; Nicholas B. La Th...; Vincenzo D’Angiol...; Anderson J. Ryan; Timothy C. Humphrey
• Keywords: Synthetic Lethality; Wee1; Ribonucleotide reductase

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.