ArticleCell death & disease2011
Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells.
Article in Cell death & disease, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 116 papers.
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Who cites it
116 citing papers in PubMed, 196 citations in OpenAlex.
- Brigimadlin versus Doxorubicin in Advanced Dedifferentiated Liposarcoma: Efficacy, Safety, and Translational Data from Brightline-1, a Randomized Phase II/III Trial.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Idasanutlin in Combination with Chemotherapy or Venetoclax in Pediatric and Young Adult Patients with Relapsed/Refractory Solid Tumors (iMATRIX Idasa): Results of a Phase I/II, Multicenter, Multi-arm Study.Targeted oncology · 2026Trial
- TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma.Nature communications · 2016Trial
- The Enigmatic Tumor Suppressor p53 Biomolecule: Its Role and Prognostic and Predictive Values in Cancer Therapy and Precision Medicine.Biomolecules · 2026Review
- Divergent transcriptional programs and constrained metabolic states reveal selective metabolic dependencies in chemoresistant luminal breast cancer.Cancer drug resistance (Alhambra, Calif.) · 2026Article
- Phenotypic plasticity in a novel set of EGFR tyrosine kinase inhibitor-adapted non-small cell lung cancer cell lines.FEBS open bio · 2025Article
- Increased efficacy of PARP inhibitors against cisplatin-sensitive and -resistant ovarian cancer cells mediated via ATR and ATM inhibition.Cell death discovery · 2025Article
- Synergistic effect of MDM2 inhibitors and radiotherapy in endometrial cancer.NPJ precision oncology · 2025Article
- Targeting the MDM2-MDM4 interaction interface reveals an otherwise therapeutically active wild-type p53 in colorectal cancer.Molecular oncology · 2025Article
- MD-4251: A First-in-Class Oral MDM2 Degrader Inducing Complete Tumor Regression with Single-Dose Administration.Journal of medicinal chemistry · 2025Article
- Review
- Artesunate Inhibits Metastatic Potential in Cisplatin-Resistant Bladder Cancer Cells by Altering Integrins.Cells · 2025Article
- Structure and function of MDM2 and MDM4 in health and disease.The Biochemical journal · 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
- MDM2 inhibitors in cancer immunotherapy: Current status and perspective.Genes & diseases · 2024Review
- Targeting mutant p53: a key player in breast cancer pathogenesis and beyond.Cell communication and signaling : CCS · 2024Review
- Cisplatin-Resistant Urothelial Bladder Cancer Cells Undergo Metabolic Reprogramming beyond the Warburg Effect.Cancers · 2024Article
- Kinome-Wide Synthetic Lethal Screen Identifies PANK4 as a Modulator of Temozolomide Resistance in Glioblastoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- New Insights into Chemoresistance Mediated by Mdm2 Inhibitors: The Benefits of Targeted Therapy over Common Cytostatics.Biomedicines · 2024Article
- Effects of Lactate Transport Inhibition by AZD3965 in Muscle-Invasive Urothelial Bladder Cancer.Pharmaceutics · 2023Article
56 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 6 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Six p53 wild-type cancer cell lines from infrequently p53-mutated entities (neuroblastoma, rhabdomyosarcoma, and melanoma) were continuously exposed to increasing concentrations of the murine double minute 2 inhibitor nutlin-3, resulting in the emergence of nutlin-3-resistant, p53-mutated sublines displaying a multi-drug resistance phenotype. Only 2 out of 28 sublines adapted to various cytotoxic drugs harboured p53 mutations. Nutlin-3-adapted UKF-NB-3 cells (UKF-NB-3(r)Nutlin(10 μM), harbouring a G245C mutation) were also radiation resistant. Analysis of UKF-NB-3 and UKF-NB-3(r)Nutlin(10 μM) cells by RNA interference experiments and lentiviral transduction of wild-type p53 into p53-mutated UKF-NB-3(r)Nutlin(10 μM) cells revealed that the loss of p53 function contributes to the multi-drug resistance of UKF-NB-3(r)Nutlin(10 μM) cells. Bioinformatics PANTHER pathway analysis based on microarray measurements of mRNA abundance indicated a substantial overlap in the signalling pathways differentially regulated between UKF-NB-3(r)Nutlin(10 μM) and UKF-NB-3 and between UKF-NB-3 and its cisplatin-, doxorubicin-, or vincristine-resistant sublines. Repeated nutlin-3 adaptation of neuroblastoma cells resulted in sublines harbouring various p53 mutations with high frequency. A p53 wild-type single cell-derived UKF-NB-3 clone was adapted to nutlin-3 in independent experiments. Eight out of ten resulting sublines were p53-mutated harbouring six different p53 mutations. This indicates that nutlin-3 induces de novo p53 mutations not initially present in the original cell population. Therefore, nutlin-3-treated cancer patients should be carefully monitored for the emergence of p53-mutated, multi-drug-resistant cells.
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