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AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations

Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are able to activate alternative signaling pathways...

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Autores principales: Meng, Xiangbing, Bi, Jianling, Li, Yujun, Yang, Shujie, Zhang, Yuping, Li, Mary, Liu, Haitao, Li, Yiyang, Mcdonald, Megan E., Thiel, Kristina W., Wen, Kuo-Kuang, Wang, Xinhao, Wu, Meng, Leslie, Kimberly K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977122/
https://www.ncbi.nlm.nih.gov/pubmed/29783721
http://dx.doi.org/10.3390/cancers10050149
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author Meng, Xiangbing
Bi, Jianling
Li, Yujun
Yang, Shujie
Zhang, Yuping
Li, Mary
Liu, Haitao
Li, Yiyang
Mcdonald, Megan E.
Thiel, Kristina W.
Wen, Kuo-Kuang
Wang, Xinhao
Wu, Meng
Leslie, Kimberly K.
author_facet Meng, Xiangbing
Bi, Jianling
Li, Yujun
Yang, Shujie
Zhang, Yuping
Li, Mary
Liu, Haitao
Li, Yiyang
Mcdonald, Megan E.
Thiel, Kristina W.
Wen, Kuo-Kuang
Wang, Xinhao
Wu, Meng
Leslie, Kimberly K.
author_sort Meng, Xiangbing
collection PubMed
description Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are able to activate alternative signaling pathways that maintain the G2/M checkpoint, which becomes uniquely critical for the survival of such tumor cells. We hypothesized that abrogation of the G2 checkpoint might preferentially sensitize p53-defective tumor cells to DNA-damaging agents and spare normal cells with intact p53 function. The tyrosine kinase WEE1 regulates cdc2 activity at the G2/M checkpoint and prevents entry into mitosis in response to DNA damage or stalled DNA replication. AZD1775 is a WEE1 inhibitor that overrides and opens the G2/M checkpoint by preventing WEE1-mediated phosphorylation of cdc2 at tyrosine 15. In this study, we assessed the effect of AZD1775 on endometrial and ovarian cancer cells in the presence of two DNA damaging agents, the PARP1 inhibitor, olaparib, and the chemotherapeutic agent, gemcitabine. We show that AZD1775 alone is effective as a therapeutic agent against some p53 mutated cell models. Moreover, the combination of AZD1775 with olaparib or gemcitabine is synergistic in cells with mutant p53 and constitutes a new approach that should be considered in the treatment of advanced and recurrent gynecologic cancer.
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spelling pubmed-59771222018-05-31 AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations Meng, Xiangbing Bi, Jianling Li, Yujun Yang, Shujie Zhang, Yuping Li, Mary Liu, Haitao Li, Yiyang Mcdonald, Megan E. Thiel, Kristina W. Wen, Kuo-Kuang Wang, Xinhao Wu, Meng Leslie, Kimberly K. Cancers (Basel) Article Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are able to activate alternative signaling pathways that maintain the G2/M checkpoint, which becomes uniquely critical for the survival of such tumor cells. We hypothesized that abrogation of the G2 checkpoint might preferentially sensitize p53-defective tumor cells to DNA-damaging agents and spare normal cells with intact p53 function. The tyrosine kinase WEE1 regulates cdc2 activity at the G2/M checkpoint and prevents entry into mitosis in response to DNA damage or stalled DNA replication. AZD1775 is a WEE1 inhibitor that overrides and opens the G2/M checkpoint by preventing WEE1-mediated phosphorylation of cdc2 at tyrosine 15. In this study, we assessed the effect of AZD1775 on endometrial and ovarian cancer cells in the presence of two DNA damaging agents, the PARP1 inhibitor, olaparib, and the chemotherapeutic agent, gemcitabine. We show that AZD1775 alone is effective as a therapeutic agent against some p53 mutated cell models. Moreover, the combination of AZD1775 with olaparib or gemcitabine is synergistic in cells with mutant p53 and constitutes a new approach that should be considered in the treatment of advanced and recurrent gynecologic cancer. MDPI 2018-05-19 /pmc/articles/PMC5977122/ /pubmed/29783721 http://dx.doi.org/10.3390/cancers10050149 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Meng, Xiangbing
Bi, Jianling
Li, Yujun
Yang, Shujie
Zhang, Yuping
Li, Mary
Liu, Haitao
Li, Yiyang
Mcdonald, Megan E.
Thiel, Kristina W.
Wen, Kuo-Kuang
Wang, Xinhao
Wu, Meng
Leslie, Kimberly K.
AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations
title AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations
title_full AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations
title_fullStr AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations
title_full_unstemmed AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations
title_short AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations
title_sort azd1775 increases sensitivity to olaparib and gemcitabine in cancer cells with p53 mutations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977122/
https://www.ncbi.nlm.nih.gov/pubmed/29783721
http://dx.doi.org/10.3390/cancers10050149
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