Oncotarget

Research Papers:

A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers

Sandra Hocke, Yang Guo, Albert Job, Michael Orth, Andreas Ziesch, Kirsten Lauber, Enrico N. De Toni, Thomas M. Gress, Andreas Herbst, Burkhard Göke and Eike Gallmeier _

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Oncotarget. 2016; 7:7080-7095. https://doi.org/10.18632/oncotarget.6857

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Abstract

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

Correspondence to:

Eike Gallmeier, e-mail: Eike.Gallmeier@med.uni-marburg.de

Keywords: ATR, POLD1, synthetic lethality, DNA repair, targeted therapy

Received: August 04, 2015    Accepted: January 01, 2016    Published: January 09, 2016

ABSTRACT

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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