Journal
CANCER CELL
Volume 28, Issue 5, Pages 557-568Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2015.09.015
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Funding
- Medical Research Council [MC_PC_12003, MC_PC_12001]
- Clarendon Scholarship
- Swiss National Science Foundation
- MRC [MC_PC_12003, G0500905, MC_PC_12001, MC_PC_12006, G9400953, MC_PC_12002, G1000807] Funding Source: UKRI
- Cancer Research UK [13058] Funding Source: researchfish
- Medical Research Council [MC_PC_12006, MC_PC_12001, MC_PC_12002, MC_PC_12003, G1000807, G9400953, G0500905] Funding Source: researchfish
- Rosetrees Trust [M271-F1] Funding Source: researchfish
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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.
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