A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers
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Sandra Hocke1, Yang Guo1, Albert Job2, Michael Orth3, Andreas Ziesch1, Kirsten Lauber3, Enrico N. De Toni1, Thomas M. Gress2, Andreas Herbst1, Burkhard Göke1, Eike Gallmeier1,2
1Department of Medicine II, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany
2Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University of Marburg, 35043 Marburg, Germany
3Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany
Eike Gallmeier, e-mail: [email protected]
Keywords: ATR, POLD1, synthetic lethality, DNA repair, targeted therapy
Received: August 04, 2015 Accepted: January 01, 2016 Published: January 09, 2016
The phosphoinositide 3-kinase-related kinase ATR represents a central checkpoint regulator and mediator of DNA-repair. Its inhibition selectively eliminates certain subsets of cancer cells in various tumor types, but the underlying genetic determinants remain enigmatic. Here, we applied a synthetic lethal screen directed against 288 DNA-repair genes using the well-defined ATR knock-in model of DLD1 colorectal cancer cells to identify potential DNA-repair defects mediating these effects. We identified a set of DNA-repair proteins, whose knockdown selectively killed ATR-deficient cancer cells. From this set, we further investigated the profound synthetic lethal interaction between ATR and POLD1. ATR-dependent POLD1 knockdown-induced cell killing was reproducible pharmacologically in POLD1-depleted DLD1 cells and a panel of other colorectal cancer cell lines by using chemical inhibitors of ATR or its major effector kinase CHK1. Mechanistically, POLD1 depletion in ATR-deficient cells caused caspase-dependent apoptosis without preceding cell cycle arrest and increased DNA-damage along with impaired DNA-repair. Our data could have clinical implications regarding tumor genotype-based cancer therapy, as inactivating POLD1 mutations have recently been identified in small subsets of colorectal and endometrial cancers. POLD1 deficiency might thus represent a predictive marker for treatment response towards ATR- or CHK1-inhibitors that are currently tested in clinical trials.
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