ArticleOncogene2011
Acquisition of p53 mutations in response to the non-genotoxic p53 activator Nutlin-3.
Article in Oncogene, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers.
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The trial behind it
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Who cites it
81 citing papers in PubMed, 133 citations in OpenAlex.
- TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma.Nature communications · 2016Trial
- Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition.Cell death and differentiation · 2025Article
- The TP53 tumor suppressor gene: From molecular biology to clinical investigations.Journal of internal medicine · 2025Review
- MD-4251: A First-in-Class Oral MDM2 Degrader Inducing Complete Tumor Regression with Single-Dose Administration.Journal of medicinal chemistry · 2025Article
- Structure and function of MDM2 and MDM4 in health and disease.The Biochemical journal · 2025Review
- Side-stepping the guardian of the genome: current cancer therapeutics targeting mutant p53.Frontiers in pharmacology · 2025Review
- BH3-mimetics or DNA-damaging agents in combination with RG7388 overcome p53 mutation-induced resistance to MDM2 inhibition.Apoptosis : an international journal on programmed cell death · 2024Article
- Targeting apoptotic pathways for cancer therapy.The Journal of clinical investigation · 2024Review
- Translating p53-based therapies for cancer into the clinic.Nature reviews. Cancer · 2024Review
- New Insights into Chemoresistance Mediated by Mdm2 Inhibitors: The Benefits of Targeted Therapy over Common Cytostatics.Biomedicines · 2024Article
- Advancements in MDM2 inhibition: Clinical and pre-clinical investigations of combination therapeutic regimens.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2023Review
- miR-221/222 induce instability of p53 By downregulating deubiquitinase YOD1 in acute myeloid leukemia.Cell death discovery · 2023Article
- Shared gene targets of the ATF4 and p53 transcriptional networks.bioRxiv : the preprint server for biology · 2023Article
- Shared Gene Targets of the ATF4 and p53 Transcriptional Networks.Molecular and cellular biology · 2023Article
- PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response.Nature communications · 2022Article
- Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?Cellular & molecular biology letters · 2021Review
- Long transcripts minus touchdown qPCR (LTMT-qPCR): a simplified and convenient method for the screening and quantification of microRNA profiles.Laboratory investigation; a journal of technical methods and pathology · 2021Article
- MI-773, a breaker of the MDM2/p53 axis, exhibits anticancer effects in neuroblastoma via downregulation of INSM1.Oncology letters · 2021Article
- Review
- The role of SIRT5 and p53 proteins in the sensitivity of colon cancer cells to chemotherapeutic agent 5-Fluorouracil.Molecular biology reports · 2021Article
21 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Wild-type p53 is a stress-responsive tumor suppressor and potent growth inhibitor. Genotoxic stresses (for example, ionizing and ultraviolet radiation or chemotherapeutic drug treatment) can activate p53, but also induce mutations in the P53 gene, and thus select for p53-mutated cells. Nutlin-3a (Nutlin) is pre-clinical drug that activates p53 in a non-genotoxic manner. Nutlin occupies the p53-binding pocket of murine double minute 2 (MDM2), activating p53 by blocking the p53-MDM2 interaction. Because Nutlin neither binds p53 directly nor introduces DNA damage, we hypothesized Nutlin would not induce P53 mutations, and, therefore, not select for p53-mutated cells. To test this, populations of SJSA-1 (p53 wild-type) cancer cells were expanded that survived repeated Nutlin exposures, and individual clones were isolated. Group 1 clones were resistant to Nutlin-induced apoptosis, but still underwent growth arrest. Surprisingly, while some Group 1 clones retained wild-type p53, others acquired a heterozygous p53 mutation. Apoptosis resistance in Group 1 clones was associated with decreased PUMA induction and decreased caspase 3/7 activation. Group 2 clones were resistant to both apoptosis and growth arrest induced by Nutlin. Group 2 clones had acquired mutations in the p53-DNA-binding domain and expressed only mutant p53s that were induced by Nutlin treatment, but were unable to bind the P21 and PUMA gene promoters, and unable to activate transcription. These results demonstrate that non-genotoxic p53 activation (for example, by Nutlin treatment) can lead to the acquisition of somatic mutations in p53 and select for p53-mutated cells. These findings have implications for the potential clinical use of Nutlin and other small molecule MDM2 antagonists.
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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.