ArticlePLoS genetics2020
Dual genome-wide CRISPR knockout and CRISPR activation screens identify mechanisms that regulate the resistance to multiple ATR inhibitors.
Article in PLoS genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
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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
19 citing papers in PubMed, 26 citations in OpenAlex.
- Replication stress in cancer: origins, consequences and therapeutic opportunities.Nature reviews. Cancer · 2026Review
- In vivo CRISPR knockout screen identifies Polr1a as a key driver and a potential therapeutic target for melanoma metastasis.Oncogene · 2026Article
- Next Generation DNA Damage Response Inhibitors: Harnessing Nanocarriers and Tumor Microenvironment for Precision Cancer Therapy.Oncology research · 2026Review
- Stochastic variation in the FOXM1 transcription program mediates replication stress tolerance.Molecular oncology · 2025Article
- Co-essentiality analysis identifies PRR12 as a cohesin interacting protein and contributor to genomic integrity.Developmental cell · 2025Article
- DNA damage response inhibitors in cancer therapy: lessons from the past, current status and future implications.Nature reviews. Drug discovery · 2025Review
- Targeting ATR in patients with cancer.Nature reviews. Clinical oncology · 2024Review
- USP1-dependent nucleolytic expansion of PRIMPOL-generated nascent DNA strand discontinuities during replication stress.Nucleic acids research · 2024Article
- TP63-TRIM29 axis regulates enhancer methylation and chromosomal instability in prostate cancer.Epigenetics & chromatin · 2024Article
- Revolutionizing DNA repair research and cancer therapy with CRISPR-Cas screens.Nature reviews. Molecular cell biology · 2023Review
- CRISPR screens guide the way for PARP and ATR inhibitor biomarker discovery.The FEBS journal · 2022Review
- ATR Inhibitors in Platinum-Resistant Ovarian Cancer.Cancers · 2022Review
- Resistance to ATR Inhibitors Is Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2.Cancer research · 2022Article
- SMG8/SMG9 Heterodimer Loss Modulates SMG1 Kinase to Drive ATR Inhibitor Resistance.Cancer research · 2022Article
- Exploring the genetic space of the DNA damage response for cancer therapy through CRISPR-based screens.Molecular oncology · 2022Review
- Aberrant R-loop-induced replication stress in MED12-mutant uterine fibroids.Scientific reports · 2022Article
- DNA repair defects in cancer and therapeutic opportunities.Genes & development · 2022Review
- The role of mediator subunit 12 in tumorigenesis and cancer therapeutics.Oncology letters · 2022Review
- Loss of MED12 activates the TGFβ pathway to promote chemoresistance and replication fork stability in BRCA-deficient cells.Nucleic acids research · 2021Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
The ataxia telangiectasia and Rad3-related (ATR) protein kinase is a key regulator of the cellular response to DNA damage. Due to increased amount of replication stress, cancer cells heavily rely on ATR to complete DNA replication and cell cycle progression. Thus, ATR inhibition is an emerging target in cancer therapy, with multiple ATR inhibitors currently undergoing clinical trials. Here, we describe dual genome-wide CRISPR knockout and CRISPR activation screens employed to comprehensively identify genes that regulate the cellular resistance to ATR inhibitors. Specifically, we investigated two different ATR inhibitors, namely VE822 and AZD6738, in both HeLa and MCF10A cells. We identified and validated multiple genes that alter the resistance to ATR inhibitors. Importantly, we show that the mechanisms of resistance employed by these genes are varied, and include restoring DNA replication fork progression, and prevention of ATR inhibitor-induced apoptosis. In particular, we describe a role for MED12-mediated inhibition of the TGFβ signaling pathway in regulating replication fork stability and cellular survival upon ATR inhibition. Our dual genome-wide screen findings pave the way for personalized medicine by identifying potential biomarkers for ATR inhibitor resistance.
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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.