ArticleNature chemical biology2016
CRISPR-Cas9-based target validation for p53-reactivating model compounds.
Article in Nature chemical biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 92 citations in OpenAlex.
- Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks.Nucleic acids research · 2016Pooled it
- Secreted luciferases as a minimally invasive 3R-compliant tool for accurate monitoring of tumor burden.Nature protocols · 2026Review
- Strategic selection of MDM2 inhibitors enhances the efficacy of FAK inhibition in mesothelioma based on TP53 genotype.PloS one · 2026Article
- The CRISPR-Cas revolution in head and neck cancer: a new era of targeted therapy.Functional & integrative genomics · 2025Review
- Targeting PI3K inhibitor resistance in breast cancer with metabolic drugs.Signal transduction and targeted therapy · 2025Article
- Remodeling of anti-tumor immunity with antibodies targeting a p53 mutant.Journal of hematology & oncology · 2024Article
- Therapeutic targeting of ARID1A-deficient cancer cells with RITA (Reactivating p53 and inducing tumor apoptosis).Cell death & disease · 2024Article
- Comparison of cell response to chromatin and DNA damage.Nucleic acids research · 2023Article
- MDM2 antagonists promote CRISPR/Cas9-mediated precise genome editing in sheep primary cells.Molecular therapy. Nucleic acids · 2023Article
- Knowledge mapping and current trends of global research on CRISPR in the field of cancer.Frontiers in cell and developmental biology · 2023Article
- Epigenetically silenced apoptosis-associated tyrosine kinase (AATK) facilitates a decreased expression of Cyclin D1 and WEE1, phosphorylates TP53 and reduces cell proliferation in a kinase-dependent manner.Cancer gene therapy · 2022Article
- Decreased DNA Damage and Improved p53 Specificity of RITA Analogs.Molecular cancer therapeutics · 2022Article
- Monitoring autochthonous lung tumors induced by somatic CRISPR gene editing in mice using a secreted luciferase.Molecular cancer · 2022Article
- The importin beta superfamily member RanBP17 exhibits a role in cell proliferation and is associated with improved survival of patients with HPV+ HNSCC.BMC cancer · 2022Article
- Article
- CRISPER/CAS System, a Novel Tool of Targeted Therapy of Drug-Resistant Lung Cancer.Advanced pharmaceutical bulletin · 2022Review
- Current Advances in CETSA.Frontiers in molecular biosciences · 2022Review
- Novel Allosteric Mechanism of Dual p53/MDM2 and p53/MDM4 Inhibition by a Small Molecule.Frontiers in molecular biosciences · 2022Article
- Article
- CRISPR-Cas deployment in non-small cell lung cancer for target screening, validations, and discoveries.Cancer gene therapy · 2021Review
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
Inactivation of the p53 tumor suppressor by Mdm2 is one of the most frequent events in cancer, so compounds targeting the p53-Mdm2 interaction are promising for cancer therapy. Mechanisms conferring resistance to p53-reactivating compounds are largely unknown. Here we show using CRISPR-Cas9-based target validation in lung and colorectal cancer that the activity of nutlin, which blocks the p53-binding pocket of Mdm2, strictly depends on functional p53. In contrast, sensitivity to the drug RITA, which binds the Mdm2-interacting N terminus of p53, correlates with induction of DNA damage. Cells with primary or acquired RITA resistance display cross-resistance to DNA crosslinking compounds such as cisplatin and show increased DNA cross-link repair. Inhibition of FancD2 by RNA interference or pharmacological mTOR inhibitors restores RITA sensitivity. The therapeutic response to p53-reactivating compounds is therefore limited by compound-specific resistance mechanisms that can be resolved by CRISPR-Cas9-based target validation and should be considered when allocating patients to p53-reactivating treatments.
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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.