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

Sophia X Pfister,Enni Markkanen,Yanyan Jiang,Sovan Sarkar,Mick Woodcock,Giulia Orlando,Ioanna Mavrommati,Chen-Chun Pai,Lykourgos-Panagiotis Zalmas,Neele Drobnitzky,Grigory L Dianov,Clare Verrill,Valentine M Macaulay,Songmin Ying,Nicholas B La Thangue,Vincenzo D’Angiolella,Anderson J Ryan,Timothy C Humphrey

doi:10.1016/j.ccell.2015.09.015

Abstract

SummaryHistone 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.

Highlights

Trimethylation of histone H3K36 (H3K36me3) is an epigenetic mark usually associated with actively transcribed genes (Shilatifard, 2006), for which proposed functions include DNA repair (Aymard et al, 2014; Carvalho et al, 2014; Pfister et al, 2014), chromatin structure modulation during elongation (Carvalho et al, 2013), and stem cell regulation (Zhang et al, 2014; Zhu et al, 2014)
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

Summary

Introduction

Trimethylation of histone H3K36 (H3K36me3) is an epigenetic mark usually associated with actively transcribed genes (Shilatifard, 2006), for which proposed functions include DNA repair (Aymard et al, 2014; Carvalho et al, 2014; Pfister et al, 2014), chromatin structure modulation during elongation (Carvalho et al, 2013), and stem cell regulation (Zhang et al, 2014; Zhu et al, 2014). SETD2 under-expression and mutation are associated with poor prognosis in breast cancer (Al Sarakbi et al, 2009) and renal cancer (Hakimi et al, 2013), and KDM4A overexpression is associated with poor patient outcome in ovarian cancer (Black et al, 2013). SETD2 mutations and KDM4A overexpression are together observed in more than 10% of cancers in kidney, large intestines, endometrium, and ovary (Berry and Janknecht, 2013; Dalgliesh et al, 2010; Gerlinger et al, 2012). Despite its frequent loss and association with poor prognosis, there is no therapy targeting H3K36me3-deficient cancers

Results

Discussion

Conclusion