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; Anderson J. Ryan; Timothy C. Humphrey; Vincenzo D'Angiolella

doi:10.1016/j.ccell.2015.09.015

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, Anderson J. Ryan, Timothy C. Humphrey, Vincenzo D'Angiolella

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Abstract

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.

Original language	English
Pages (from-to)	557-568
Journal	Cancer Cell
Volume	28
Issue number	5
Early online date	22 Oct 2015
DOIs	https://doi.org/10.1016/j.ccell.2015.09.015
Publication status	Published - 9 Nov 2015

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Pfister, SX., Markkanen, E., Jiang, Y., Sarkar, S., Woodcock, M., Orlando, G., Mavrommati, I., Pai, C.-C., Zalmas, L.-P., Drobnitzky, N., Dianov, GL., Verrill, C., Macaulay, VM., Ying, S., La Thangue, NB., Ryan, AJ., Humphrey, TC., & D'Angiolella, V. (2015). Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation. Cancer Cell, 28(5), 557-568. https://doi.org/10.1016/j.ccell.2015.09.015

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title = "Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation",

abstract = "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.",

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

year = "2015",

month = nov,

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doi = "10.1016/j.ccell.2015.09.015",

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Pfister, SX, Markkanen, E, Jiang, Y, Sarkar, S, Woodcock, M, Orlando, G, Mavrommati, I, Pai, C-C, Zalmas, L-P, Drobnitzky, N, Dianov, GL, Verrill, C, Macaulay, VM, Ying, S, La Thangue, NB, Ryan, AJ, Humphrey, TC & D'Angiolella, V 2015, 'Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation', Cancer Cell, vol. 28, no. 5, pp. 557-568. https://doi.org/10.1016/j.ccell.2015.09.015

TY - JOUR

T1 - Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation

AU - Pfister, Sophia X.

AU - Markkanen, Enni

AU - Jiang, Yanyan

AU - Sarkar, Sovan

AU - Woodcock, Mick

AU - Orlando, Giulia

AU - Mavrommati, Ioanna

AU - Pai, Chen-Chun

AU - Zalmas, Lykourgos-Panagiotis

AU - Drobnitzky, Neele

AU - Dianov, Grigory L.

AU - Verrill, Clare

AU - Macaulay, Valentine M.

AU - Ying, Songmin

AU - La Thangue, Nicholas B.

AU - Ryan, Anderson J.

AU - Humphrey, Timothy C.

AU - D'Angiolella, Vincenzo

PY - 2015/11/9

Y1 - 2015/11/9

N2 - 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.

AB - 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.

U2 - 10.1016/j.ccell.2015.09.015

DO - 10.1016/j.ccell.2015.09.015

M3 - Article

SN - 1535-6108

VL - 28

SP - 557

EP - 568

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

Abstract

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