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.
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences and The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Wilsker
authors.forename: Jon H
authors.initials: JH
authors.lastname: Chung
authors.forename: Ivan
authors.initials: I
authors.lastname: Pradilla
authors.forename: Eva
authors.initials: E
authors.lastname: Petermann
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.forename: Fred
authors.initials: F
authors.lastname: Bunz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D000071877:Checkpoint Kinase 1; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
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