A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments.

Mohni KN, Thompson PS, Luzwick JW, Glick GG, Pendleton CS, Lehmann BD, Pietenpol JA, Cortez D
PLoS One. 2015 10 (5): e0125482

PMID: 25965342 · PMCID: PMC4428765 · DOI:10.1371/journal.pone.0125482

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 ΞΆ 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.

MeSH Terms (18)

Antineoplastic Agents Antineoplastic Combined Chemotherapy Protocols Ataxia Telangiectasia Mutated Proteins Cell Line, Tumor Cell Survival Cisplatin DNA-Directed DNA Polymerase DNA Repair Drug Resistance, Neoplasm Drug Synergism Gene Library HCT116 Cells Humans Intracellular Signaling Peptides and Proteins Pyrazines RNA, Small Interfering Sulfones Tumor Suppressor p53-Binding Protein 1

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