ArticleOncotarget2016
A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
21 citing papers in PubMed, 41 citations in OpenAlex.
- The DNA replication checkpoint limits Okazaki fragment accumulation to protect and restart stalled forks.Molecular cell · 2025Article
- Transferrin Receptor-Mediated Iron Uptake Promotes Colon Tumorigenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- ATR Inhibitors in Platinum-Resistant Ovarian Cancer.Cancers · 2022Review
- Article
- Therapeutic Opportunities of Disrupting Genome Integrity in Adult Diffuse Glioma.Biomedicines · 2022Review
- POLE, POLD1, and NTHL1: the last but not the least hereditary cancer-predisposing genes.Oncogene · 2021Review
- Sensitivity of cells to ATR and CHK1 inhibitors requires hyperactivation of CDK2 rather than endogenous replication stress or ATM dysfunction.Scientific reports · 2021Article
- The Ubiquitin Ligase TRAIP: Double-Edged Sword at the Replisome.Trends in cell biology · 2021Review
- The POLD1Scientific reports · 2020Article
- Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2020Article
- Review
- Article
- CHK1 Inhibition Is Synthetically Lethal with Loss of B-Family DNA Polymerase Function in Human Lung and Colorectal Cancer Cells.Cancer research · 2020Article
- Structural Basis for Inhibition of Human Primase by Arabinofuranosyl Nucleoside Analogues Fludarabine and Vidarabine.ACS chemical biology · 2019Article
- Inactivation of PRIM1 Function Sensitizes Cancer Cells to ATR and CHK1 Inhibitors.Neoplasia (New York, N.Y.) · 2018Article
- Reduced expression of DNA repair genes and chemosensitivity in 1p19q codeleted lower-grade gliomas.Journal of neuro-oncology · 2018Article
- Targeting epigenetics using synthetic lethality in precision medicine.Cellular and molecular life sciences : CMLS · 2018Review
- ATR/CHK1 inhibitors and cancer therapy.Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology · 2018Review
- Directing the use of DDR kinase inhibitors in cancer treatment.Expert opinion on investigational drugs · 2017Review
- Targeting the ATR-CHK1 Axis in Cancer Therapy.Cancers · 2017Review
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.