ArticleInternational journal of cancer2017
Nutlin-3a selects for cells harbouring TP53 mutations.
Article in International journal of cancer, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
- Genomic landscape and tumor immune microenvironment of osteosarcoma: Bridging mechanistic insights to precision therapeutics.Bone reports · 2026Review
- Activity-based selection for enhanced base editor mutational scanning.Nature genetics · 2025Article
- Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition.Cell death and differentiation · 2025Article
- Dichloroacetate enhances Chemo-sensitivity in wild-type P53 breast cancer cells by modulating ABCG2 and NKG2DL.Scientific reports · 2025Article
- Patient-derived organoids in non-small cell lung cancer: advances in drug sensitivity testing.Frontiers in pharmacology · 2025Review
- Age-specific induction of mutant p53 drives clonal hematopoiesis and acute myeloid leukemia in adult mice.Cell reports. Medicine · 2024Article
- β-catenin mediates growth defects induced by centrosome loss in a subset of APC mutant colorectal cancer independently of p53.PloS one · 2024Article
- DNA methylation profiling deciphers three EMT subtypes with distinct prognoses and therapeutic vulnerabilities in breast cancer.Journal of Cancer · 2024Article
- SPINK2 Protein Expression Is an Independent Adverse Prognostic Marker in AML and Is Potentially Implicated in the Regulation of Ferroptosis and Immune Response.International journal of molecular sciences · 2023Article
- FAM193A is a positive regulator of p53 activity.Cell reports · 2023Article
- Selective protection of normal cells from chemotherapy, while killing drug-resistant cancer cells.Oncotarget · 2023Review
- Characterizing the secretome of EGFR mutant lung adenocarcinoma.Frontiers in oncology · 2023Article
- PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response.Nature communications · 2022Article
- Review
- Derivation of induced pluripotent stem cell lines from New Zealand donors.Journal of the Royal Society of New Zealand · 2022Article
- Where We Stand With Precision Therapeutics in Myeloma: Prosperity, Promises, and Pipedreams.Frontiers in oncology · 2021Review
- Characterization of acquired nutlin-3 resistant non-small cell lung cancer cells.Cancer drug resistance (Alhambra, Calif.) · 2021Article
- Mutagenicity of acrylamide and glycidamide in human TP53 knock-in (Hupki) mouse embryo fibroblasts.Archives of toxicology · 2020Article
- Conditional reprogramming: Modeling urological cancer and translation to clinics.Clinical and translational medicine · 2020Review
- Characterising Mutational Spectra of Carcinogens in the Tumour Suppressor GeneMethods and protocols · 2019Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 3 countries.
Funding
Abstract
TP53 mutations occur in half of all human tumours. Mutagen-induced or spontaneous TP53 mutagenesis can be studied in vitro using the human TP53 knock-in (Hupki) mouse embryo fibroblast (HUF) immortalisation assay (HIMA). TP53 mutations arise in up to 30% of mutagen-treated, immortalised HUFs; however, mutants are not identified until TP53 sequence analysis following immortalisation (2-5 months) and much effort is expended maintaining TP53-WT cultures. In order to improve the selectivity of the HIMA for HUFs harbouring TP53 mutations, we explored the use of Nutlin-3a, an MDM2 inhibitor that leads to stabilisation and activation of wild-type (WT) p53. First, we treated previously established immortal HUF lines carrying WT or mutated TP53 with Nutlin-3a to examine the effect on cell growth and p53 activation. Nutlin-3a induced the p53 pathway in TP53-WT HUFs and inhibited cell growth, whereas most TP53-mutated HUFs were resistant to Nutlin-3a. We then assessed whether Nutlin-3a treatment could discriminate between TP53-WT and TP53-mutated cells during the HIMA (n = 72 cultures). As immortal clones emerged from senescent cultures, each was treated with 10 µM Nutlin-3a for 5 days and observed for sensitivity or resistance. TP53 was subsequently sequenced from all immortalised clones. We found that all Nutlin-3a-resistant clones harboured TP53 mutations, which were diverse in position and functional impact, while all but one of the Nutlin-3a-sensitive clones were TP53-WT. These data suggest that including a Nutlin-3a counter-screen significantly improves the specificity and efficiency of the HIMA, whereby TP53-mutated clones are selected prior to sequencing and TP53-WT clones can be discarded.
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Registered trials
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