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Forced Mitotic Entry of S-Phase Cells as a Therapeutic Strategy Induced by Inhibition of WEE1

Forced Mitotic Entry of S-Phase Cells as a Therapeutic Strategy Induced by Inhibition of WEE1 Inhibition of the protein kinase WEE1 synergizes with chemotherapy in preclinical models and WEE1 inhibitors are being explored as potential cancer therapies. Here, we investigate the mechanism that underlies this synergy. We show that WEE1 inhibition forces S-phase–arrested cells directly into mitosis without completing DNA synthesis, resulting in highly abnormal mitoses characterized by dispersed chromosomes and disorganized bipolar spindles, ultimately resulting in mitotic exit with gross micronuclei formation and apoptosis. This mechanism of cell death is shared by CHK1 inhibitors, and combined WEE1 and CHK1 inhibition forces mitotic entry from S-phase in the absence of chemotherapy. We show that p53/p21 inactivation combined with high expression of mitotic cyclins and EZH2 predispose to mitotic entry during S-phase with cells reliant on WEE1 to prevent premature cyclin-dependent kinase (CDK)1 activation. These features are characteristic of aggressive breast, and other, cancers for which WEE1 inhibitor combinations represent a promising targeted therapy. Significance: Here, we describe a novel mechanism of inducing cancer cell death by WEE1 inhibition, forcing mitotic entry directly from S-phase. This mechanism represents a potential therapeutic approach for aggressive breast cancers, and in particular triple-negative and basal-like breast cancers, as WEE1 inhibition specifically targets the features inherent in these cancers: frequent TP53 mutation and high expression of mitotic cyclins and the polycomb protein EZH2. Cancer Discov; 2(6); 524–39. © 2012 AACR. This article is highlighted in the In This Issue feature, p. 473 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Discovery American Association of Cancer Research

Forced Mitotic Entry of S-Phase Cells as a Therapeutic Strategy Induced by Inhibition of WEE1

Forced Mitotic Entry of S-Phase Cells as a Therapeutic Strategy Induced by Inhibition of WEE1

Cancer Discovery , Volume 2 (6): 16 – Jun 1, 2012

Abstract

Inhibition of the protein kinase WEE1 synergizes with chemotherapy in preclinical models and WEE1 inhibitors are being explored as potential cancer therapies. Here, we investigate the mechanism that underlies this synergy. We show that WEE1 inhibition forces S-phase–arrested cells directly into mitosis without completing DNA synthesis, resulting in highly abnormal mitoses characterized by dispersed chromosomes and disorganized bipolar spindles, ultimately resulting in mitotic exit with gross micronuclei formation and apoptosis. This mechanism of cell death is shared by CHK1 inhibitors, and combined WEE1 and CHK1 inhibition forces mitotic entry from S-phase in the absence of chemotherapy. We show that p53/p21 inactivation combined with high expression of mitotic cyclins and EZH2 predispose to mitotic entry during S-phase with cells reliant on WEE1 to prevent premature cyclin-dependent kinase (CDK)1 activation. These features are characteristic of aggressive breast, and other, cancers for which WEE1 inhibitor combinations represent a promising targeted therapy. Significance: Here, we describe a novel mechanism of inducing cancer cell death by WEE1 inhibition, forcing mitotic entry directly from S-phase. This mechanism represents a potential therapeutic approach for aggressive breast cancers, and in particular triple-negative and basal-like breast cancers, as WEE1 inhibition specifically targets the features inherent in these cancers: frequent TP53 mutation and high expression of mitotic cyclins and the polycomb protein EZH2. Cancer Discov; 2(6); 524–39. © 2012 AACR. This article is highlighted in the In This Issue feature, p. 473

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Publisher
American Association of Cancer Research
Copyright
©2012 American Association for Cancer Research.
ISSN
2159-8274
eISSN
2159-8290
DOI
10.1158/2159-8290.cd-11-0320
Publisher site
See Article on Publisher Site

Abstract

Inhibition of the protein kinase WEE1 synergizes with chemotherapy in preclinical models and WEE1 inhibitors are being explored as potential cancer therapies. Here, we investigate the mechanism that underlies this synergy. We show that WEE1 inhibition forces S-phase–arrested cells directly into mitosis without completing DNA synthesis, resulting in highly abnormal mitoses characterized by dispersed chromosomes and disorganized bipolar spindles, ultimately resulting in mitotic exit with gross micronuclei formation and apoptosis. This mechanism of cell death is shared by CHK1 inhibitors, and combined WEE1 and CHK1 inhibition forces mitotic entry from S-phase in the absence of chemotherapy. We show that p53/p21 inactivation combined with high expression of mitotic cyclins and EZH2 predispose to mitotic entry during S-phase with cells reliant on WEE1 to prevent premature cyclin-dependent kinase (CDK)1 activation. These features are characteristic of aggressive breast, and other, cancers for which WEE1 inhibitor combinations represent a promising targeted therapy. Significance: Here, we describe a novel mechanism of inducing cancer cell death by WEE1 inhibition, forcing mitotic entry directly from S-phase. This mechanism represents a potential therapeutic approach for aggressive breast cancers, and in particular triple-negative and basal-like breast cancers, as WEE1 inhibition specifically targets the features inherent in these cancers: frequent TP53 mutation and high expression of mitotic cyclins and the polycomb protein EZH2. Cancer Discov; 2(6); 524–39. © 2012 AACR. This article is highlighted in the In This Issue feature, p. 473

Journal

Cancer DiscoveryAmerican Association of Cancer Research

Published: Jun 1, 2012

References