A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers.
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.
Mesh Terms:
Ataxia Telangiectasia Mutated Proteins, Blotting, Western, Cell Cycle, Cell Nucleus, Cell Proliferation, Colorectal Neoplasms, DNA Damage, DNA Polymerase III, DNA Repair, DNA Repair Enzymes, Enzyme Inhibitors, Fluorometry, High-Throughput Screening Assays, Histones, Humans, Mutation, Protein Kinases, RNA, Small Interfering, Signal Transduction, Tumor Cells, Cultured
Ataxia Telangiectasia Mutated Proteins, Blotting, Western, Cell Cycle, Cell Nucleus, Cell Proliferation, Colorectal Neoplasms, DNA Damage, DNA Polymerase III, DNA Repair, DNA Repair Enzymes, Enzyme Inhibitors, Fluorometry, High-Throughput Screening Assays, Histones, Humans, Mutation, Protein Kinases, RNA, Small Interfering, Signal Transduction, Tumor Cells, Cultured
Oncotarget
Date: Feb. 09, 2016
PubMed ID: 26755646
View in: Pubmed Google Scholar
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