Targeted mutations in the ATR pathway define agent-specific requirements for cancer cell growth and survival

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Targeted mutations in the ATR pathway define agent-specific requirements for cancer cell growth and survival. / Wilsker, Deborah; Chung, Jon H; Pradilla, Ivan; Petermann, Eva; Helleday, Thomas; Petermann, Eva; Bunz, Fred.

In: Molecular Cancer Therapeutics, Vol. 11, No. 1, 01.2012, p. 98-107.

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Wilsker, Deborah ; Chung, Jon H ; Pradilla, Ivan ; Petermann, Eva ; Helleday, Thomas ; Petermann, Eva ; Bunz, Fred. / Targeted mutations in the ATR pathway define agent-specific requirements for cancer cell growth and survival. In: Molecular Cancer Therapeutics. 2012 ; Vol. 11, No. 1. pp. 98-107.

Bibtex

@article{0d89a7ae279e483887299f4494441739,
title = "Targeted mutations in the ATR pathway define agent-specific requirements for cancer cell growth and survival",
abstract = "Many anticancer agents induce DNA strand breaks or cause the accumulation of DNA replication intermediates. The protein encoded by ataxia-telangiectasia mutated and Rad 3-related (ATR) generates signals in response to these altered DNA structures and activates cellular survival responses. Accordingly, ATR has drawn increased attention as a potential target for novel therapeutic strategies designed to potentiate the effects of existing drugs. In this study, we use a unique panel of genetically modified human cancer cells to unambiguously test the roles of upstream and downstream components of the ATR pathway in the responses to common therapeutic agents. Upstream, the S-phase-specific cyclin-dependent kinase (Cdk) 2 was required for robust activation of ATR in response to diverse chemotherapeutic agents. While Cdk2-mediated ATR activation promoted cell survival after treatment with many drugs, signaling from ATR directly to the checkpoint kinase Chk1 was required for survival responses to only a subset of the drugs tested. These results show that specifically inhibiting the Cdk2/ATR/Chk1 pathway via distinct regulators can differentially sensitize cancer cells to a wide range of therapeutic agents.",
keywords = "Antineoplastic Agents, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Cell Survival, Colonic Neoplasms, Cyclin-Dependent Kinase 2, Humans, Protein Kinases, Protein-Serine-Threonine Kinases, Signal Transduction",
author = "Deborah Wilsker and Chung, {Jon H} and Ivan Pradilla and Eva Petermann and Thomas Helleday and Eva Petermann and Fred Bunz",
note = "{\textcopyright}2011 AACR.",
year = "2012",
month = jan,
doi = "10.1158/1535-7163.MCT-11-0675",
language = "English",
volume = "11",
pages = "98--107",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research",
number = "1",

}

RIS

TY - JOUR

T1 - Targeted mutations in the ATR pathway define agent-specific requirements for cancer cell growth and survival

AU - Wilsker, Deborah

AU - Chung, Jon H

AU - Pradilla, Ivan

AU - Petermann, Eva

AU - Helleday, Thomas

AU - Petermann, Eva

AU - Bunz, Fred

N1 - ©2011 AACR.

PY - 2012/1

Y1 - 2012/1

N2 - Many anticancer agents induce DNA strand breaks or cause the accumulation of DNA replication intermediates. The protein encoded by ataxia-telangiectasia mutated and Rad 3-related (ATR) generates signals in response to these altered DNA structures and activates cellular survival responses. Accordingly, ATR has drawn increased attention as a potential target for novel therapeutic strategies designed to potentiate the effects of existing drugs. In this study, we use a unique panel of genetically modified human cancer cells to unambiguously test the roles of upstream and downstream components of the ATR pathway in the responses to common therapeutic agents. Upstream, the S-phase-specific cyclin-dependent kinase (Cdk) 2 was required for robust activation of ATR in response to diverse chemotherapeutic agents. While Cdk2-mediated ATR activation promoted cell survival after treatment with many drugs, signaling from ATR directly to the checkpoint kinase Chk1 was required for survival responses to only a subset of the drugs tested. These results show that specifically inhibiting the Cdk2/ATR/Chk1 pathway via distinct regulators can differentially sensitize cancer cells to a wide range of therapeutic agents.

AB - Many anticancer agents induce DNA strand breaks or cause the accumulation of DNA replication intermediates. The protein encoded by ataxia-telangiectasia mutated and Rad 3-related (ATR) generates signals in response to these altered DNA structures and activates cellular survival responses. Accordingly, ATR has drawn increased attention as a potential target for novel therapeutic strategies designed to potentiate the effects of existing drugs. In this study, we use a unique panel of genetically modified human cancer cells to unambiguously test the roles of upstream and downstream components of the ATR pathway in the responses to common therapeutic agents. Upstream, the S-phase-specific cyclin-dependent kinase (Cdk) 2 was required for robust activation of ATR in response to diverse chemotherapeutic agents. While Cdk2-mediated ATR activation promoted cell survival after treatment with many drugs, signaling from ATR directly to the checkpoint kinase Chk1 was required for survival responses to only a subset of the drugs tested. These results show that specifically inhibiting the Cdk2/ATR/Chk1 pathway via distinct regulators can differentially sensitize cancer cells to a wide range of therapeutic agents.

KW - Antineoplastic Agents

KW - Ataxia Telangiectasia Mutated Proteins

KW - Cell Cycle Proteins

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Cell Survival

KW - Colonic Neoplasms

KW - Cyclin-Dependent Kinase 2

KW - Humans

KW - Protein Kinases

KW - Protein-Serine-Threonine Kinases

KW - Signal Transduction

U2 - 10.1158/1535-7163.MCT-11-0675

DO - 10.1158/1535-7163.MCT-11-0675

M3 - Article

C2 - 22084169

VL - 11

SP - 98

EP - 107

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 1

ER -