ArticleProceedings of the National Academy of Sciences of the United States of America2022
Synthetical lethality of Werner helicase and mismatch repair deficiency is mediated by p53 and PUMA in colon cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 21 papers.
What it found
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Who cites it
21 citing papers in PubMed, 30 citations in OpenAlex.
- Targeting WRN Helicase in Microsatellite-Instable Colorectal Cancer Induces Antitumor Immunity through Extrachromosomal Circular DNA Release.Cancer research · 2026Article
- Increased vulnerability of colorectal cancer models with high alkylation damage to NTHL1 inactivation.Scientific reports · 2026Article
- Colorectal Adenocarcinoma: A Comprehensive Narrative Review of Molecular Pathogenesis, Metabolic Vulnerabilities, and Therapeutic Potential of Sorghum Polyphenols.Analytical cellular pathology (Amsterdam) · 2026Review
- Pan-Cancer Analysis of WRN: From Multi-Omics Biomarker Discovery to Therapy-Guiding Functional Evidence.OncoTargets and therapy · 2026Article
- Targeting DNA repair mechanisms in cancer therapy: the role of small molecule DNA repair inhibitors.NAR cancer · 2025Review
- DDX27 in cancer: molecular mechanisms, clinical implications, and therapeutic potential.Journal of translational medicine · 2025Review
- Targeting the Werner syndrome protein in microsatellite instability cancers: mechanisms and therapeutic potential.Clinical and experimental medicine · 2025Review
- PRMT5 Inhibitor Synergizes with Chemotherapy to Induce Resembling Mismatch Repair Deficiency and Enhance Anti-TIGIT Therapy in Microsatellite-Stable Colorectal Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Quinazoline Derivative kzl052 Suppresses Prostate Cancer by Targeting WRN Helicase to Stabilize DNA Replication Forks.International journal of molecular sciences · 2025Article
- p53 in colorectal cancer: from a master player to a privileged therapy target.Journal of translational medicine · 2025Review
- Werner helicase as a therapeutic target in mismatch repair deficient colorectal cancer.DNA repair · 2025Review
- Design and synthesis of N-aryl-2-trifluoromethyl-quinazoline-4-amine derivatives as potential Werner-dependent antiproliferative agents.Molecular diversity · 2025Article
- Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells.Cancer discovery · 2024Article
- Review
- Microsatellite instability: A 2024 update.Cancer science · 2024Review
- Article
- The Tumor Microenvironment: Signal Transduction.Biomolecules · 2024Review
- Comprehensive mapping of cell fates in microsatellite unstable cancer cells supports dual targeting of WRN and ATR.Genes & development · 2023Article
- Editorial: DNA repair and nucleic acid therapeutics in cancer.NAR cancer · 2023Article
- Review
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Synthetic lethality is a powerful approach for targeting oncogenic drivers in cancer. Recent studies revealed that cancer cells with microsatellite instability (MSI) require Werner (WRN) helicase for survival; however, the underlying mechanism remains unclear. In this study, we found that WRN depletion strongly induced p53 and its downstream apoptotic target PUMA in MSI colorectal cancer (CRC) cells. p53 or PUMA deletion abolished apoptosis induced by WRN depletion in MSI CRC cells. Importantly, correction of MSI abrogated the activation of p53/PUMA and cell killing, while induction of MSI led to sensitivity in isogenic CRC cells. Rare p53-mutant MSI CRC cells are resistant to WRN depletion due to lack of PUMA induction, which could be restored by wildtype (WT) p53 knock in or reconstitution. WRN depletion or treatment with the RecQ helicase inhibitor ML216 suppressed in vitro and in vivo growth of MSI CRCs in a p53/PUMA-dependent manner. ML216 treatment was efficacious in MSI CRC patient-derived xenografts. Interestingly,
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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.