title: A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments.
abstract: The DNA damage response kinase ATR may be a useful cancer therapeutic target. ATR inhibition synergizes with loss of ERCC1, ATM, XRCC1 and DNA damaging chemotherapy agents. Clinical trials have begun using ATR inhibitors in combination with cisplatin. Here we report the first synthetic lethality screen with a combination treatment of an ATR inhibitor (ATRi) and cisplatin. Combination treatment with ATRi/cisplatin is synthetically lethal with loss of the TLS polymerase ζ and 53BP1. Other DNA repair pathways including homologous recombination and mismatch repair do not exhibit synthetic lethal interactions with ATRi/cisplatin, even though loss of some of these repair pathways sensitizes cells to cisplatin as a single-agent. We also report that ATRi strongly synergizes with PARP inhibition, even in homologous recombination-proficient backgrounds. Lastly, ATR inhibitors were able to resensitize cisplatin-resistant cell lines to cisplatin. These data provide a comprehensive analysis of DNA repair pathways that exhibit synthetic lethality with ATR inhibitors when combined with cisplatin chemotherapy, and will help guide patient selection strategies as ATR inhibitors progress into the cancer clinic.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Kareem N
authors.initials: KN
authors.lastname: Mohni
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Petria S
authors.initials: PS
authors.lastname: Thompson
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Jessica W
authors.initials: JW
authors.lastname: Luzwick
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Gloria G
authors.initials: GG
authors.lastname: Glick
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Pendleton
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lehmann
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pietenpol
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Cortez
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects*; D004259:DNA-Directed DNA Polymerase; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D015723:Gene Library; D045325:HCT116 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D011719:Pyrazines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: C560580:3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide; D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D011719:Pyrazines; D034741:RNA, Small Interfering; D013450:Sulfones; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C425929:DNA polymerase zeta; D004259:DNA-Directed DNA Polymerase; D002945:Cisplatin