ArticleProceedings of the National Academy of Sciences of the United States of America2023
CRISPR metabolic screen identifies ATM and KEAP1 as targetable genetic vulnerabilities in solid tumors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 18 citations in OpenAlex.
- Targeting ubiquitin signaling vulnerabilities in KEAP1-inactivated lung cancer.The EMBO journal · 2026Article
- Targeting metabolism to combat anticancer and antibacterial drug resistance.Trends in pharmacological sciences · 2026Review
- Defining treatment-resistant brain cancer: Genetic screening to identify oncogene-driven immunomodulation and therapy resistance.Cancer gene therapy · 2026Review
- Targeting NRF2 addiction in cancer: synthetic lethal strategies beyond direct inhibition.Frontiers in cell and developmental biology · 2026Review
- Phase separation of ERCC6L2-CtIP regulates the extent of DNA end resection.Nature cell biology · 2025Article
- Perturbomics: CRISPR-Cas screening-based functional genomics approach for drug target discovery.Experimental & molecular medicine · 2025Review
- Advancements in CRISPR/Cas systems for disease treatment.Acta pharmaceutica Sinica. B · 2025Review
- Unraveling the nexus: Genomic instability and metabolism in cancer.Cell reports · 2025Review
- Finding a needle in a haystack: functional screening for novel targets in cancer immunology and immunotherapies.Oncogene · 2025Review
- Elucidating the role of CYFIP2 in conferring cisplatin resistance in esophageal squamous cell carcinoma.Scientific reports · 2024Article
- Metabolism-focused CRISPR screen unveils mitochondrial pyruvate carrier 1 as a critical driver for PARP inhibitor resistance in lung cancer.Molecular carcinogenesis · 2024Article
- The golden key to open mystery boxes of SMARCA4-deficient undifferentiated thoracic tumor: focusing immunotherapy, tumor microenvironment and epigenetic regulation.Cancer gene therapy · 2024Review
- Regulation of antioxidants in cancer.Molecular cell · 2024Review
- Application and research progress of synthetic lethality in the development of anticancer therapeutic drugs.Frontiers in oncology · 2024Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
Cancer treatments targeting DNA repair deficiencies often encounter drug resistance, possibly due to alternative metabolic pathways that counteract the most damaging effects. To identify such alternative pathways, we screened for metabolic pathways exhibiting synthetic lethality with inhibition of the DNA damage response kinase Ataxia-telangiectasia-mutated (ATM) using a metabolism-centered Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 library. Our data revealed Kelch-like ECH-associated protein 1 (KEAP1) as a key factor involved in desensitizing cancer cells to ATM inhibition both in vitro and in vivo. Cells depleted of KEAP1 exhibited an aberrant overexpression of the cystine transporter SLC7A11, robustly accumulated cystine inducing disulfide stress, and became hypersensitive to ATM inhibition. These hallmarks were reversed in a reducing cellular environment indicating that disulfide stress was a crucial factor. In The Cancer Genome Atlas (TCGA) pan-cancer datasets, we found that ATM levels negatively correlated with KEAP1 levels across multiple solid malignancies. Together, our results unveil ATM and KEAP1 as new targetable vulnerabilities in solid tumors.
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