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

Mol Cancer Ther. 2012 Jan;11(1):98-107. doi: 10.1158/1535-7163.MCT-11-0675. Epub 2011 Nov 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor / drug effects
  • Cell Proliferation
  • Cell Survival
  • Checkpoint Kinase 1
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology*
  • Cyclin-Dependent Kinase 2 / metabolism*
  • Humans
  • Protein Kinases / metabolism*
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction / genetics

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Protein Kinases
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Protein Serine-Threonine Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2