ArticleCancer discovery2023
Targeted MDM2 Degradation Reveals a New Vulnerability for p53-Inactivated Triple-Negative Breast Cancer.
Article in Cancer discovery, 2023. 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 71 papers.
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The trial behind it
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
71 citing papers in PubMed, 96 citations in OpenAlex.
- Milademetan in Advanced Solid Tumors with MDM2 Amplification and Wild-type TP53: Preclinical and Phase II Clinical Trial Results.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- Targeted proteoform degradation for precision drug design, delivery, and therapy.Drug delivery · 2026Review
- CMLPS-N1: a novel preclinical cell line model for canine mammary tumor and its application in therapeutic screening.The veterinary quarterly · 2026Article
- KT-253, a highly potent and selective MDM2 protein degrader, eliminates malignant myelofibrosis stem/progenitor cells.Leukemia · 2026Article
- BMAL1 silencing as a promising chemosensitizing strategy for triple-negative breast cancer.Acta pharmacologica Sinica · 2026Article
- Intratumoral Mycobacterium abscessus promotes cytidine deaminase mutagenesis in non-small cell lung cancer.Signal transduction and targeted therapy · 2026Article
- An antibody-PROTAC conjugate targets BRD4/c-Myc/PD-L1 to enhance immunotherapy efficacy in triple-negative breast cancer.Cell reports. Medicine · 2026Article
- Cytotoxic Activity and In Silico Study of Secondary Metabolites Derived fromMarine drugs · 2026Article
- Harnessing MDM2-Mediated Targeted Degradation of Transcriptional and Epigenetic Machinery to Disrupt Oncogenic Addictions in Pediatric Sarcoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- MYC in Oncogenesis and Therapeutic Implications.MedComm · 2026Review
- SIVA1 Knockdown Drives Aggressive Phenotypes in Triple-Negative Breast Cancer Cells while Enhancing Paclitaxel Efficacy.ACS omega · 2026Article
- PROTAC-mediated regulation of programmed cell death: From molecular mechanisms to therapeutic breakthroughs.Innovation (Cambridge (Mass.)) · 2026Review
- MDM2 degraders for Merkel cell carcinoma: round peg in a round hole.The Journal of clinical investigation · 2026Article
- Article
- Targeted degradation of MDM2 overcomes feedback regulation of p53 signaling in Merkel cell carcinoma models.The Journal of clinical investigation · 2026Article
- Harnessing p53 for Proximity Killing.International journal of molecular sciences · 2026Review
- Apoptosis signaling and cancer targeted therapy: from bench to bespoke.Translational cancer research · 2026Review
- Article
- Targeting breast cancer senescence in 3D models of bone metastasis.Breast cancer (Tokyo, Japan) · 2026Article
- Research Progress of PROTACs in Breast Cancer: Subtype-Oriented Target Landscape, Clinical Stratification Evidence, and Engineering Strategies for Translation.Biomedicines · 2026Review
11 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Triple-negative breast cancers (TNBC) frequently inactivate p53, increasing their aggressiveness and therapy resistance. We identified an unexpected protein vulnerability in p53-inactivated TNBC and designed a new PROteolysis TArgeting Chimera (PROTAC) to target it. Our PROTAC selectively targets MDM2 for proteasome-mediated degradation with high-affinity binding and VHL recruitment. MDM2 loss in p53 mutant/deleted TNBC cells in two-dimensional/three-dimensional culture and TNBC patient explants, including relapsed tumors, causes apoptosis while sparing normal cells. Our MDM2-PROTAC is stable in vivo, and treatment of TNBC xenograft-bearing mice demonstrates tumor on-target efficacy with no toxicity to normal cells, significantly extending survival. Transcriptomic analyses revealed upregulation of p53 family target genes. Investigations showed activation and a required role for TAp73 to mediate MDM2-PROTAC-induced apoptosis. Our data, challenging the current MDM2/p53 paradigm, show MDM2 is required for p53-inactivated TNBC cell survival, and PROTAC-targeted MDM2 degradation is an innovative potential therapeutic strategy for TNBC and superior to existing MDM2 inhibitors. SIGNIFICANCE: p53-inactivated TNBC is an aggressive, therapy-resistant, and lethal breast cancer subtype. We designed a new compound targeting an unexpected vulnerability we identified in TNBC. Our MDM2-targeted degrader kills p53-inactivated TNBC cells, highlighting the requirement for MDM2 in TNBC cell survival and as a new therapeutic target for this disease. See related commentary by Peuget and Selivanova, p. 1043. This article is highlighted in the In This Issue feature, p. 1027.
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What OpenQuestion holds
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.