ArticleBreast cancer research : BCR2021
First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models.
Article in Breast cancer research : BCR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 65 citations in OpenAlex.
- RING finger E3 ubiquitin ligases: novel therapeutic opportunities in melanoma.Cellular & molecular biology letters · 2026Review
- Hitting pause on chemotherapy-induced alopecia: transient p53 activation as a guardian of the hair follicle.The Journal of clinical investigation · 2026Article
- p53: from understanding its structure to advances in therapeutic targeting.Signal transduction and targeted therapy · 2026Review
- MDM2 in Tumor Biology and Cancer Therapy: A Review of Current Clinical Trials.International journal of molecular sciences · 2025Review
- Reduced structural rigidity of MDMX protein enhances binding to TP53 mRNA.Bioscience reports · 2025Article
- Dual functionality of MDM2 in PROTACs expands the horizons of targeted protein degradation.Biomarker research · 2025Review
- Discovery of a Phenylalanine-Derived Natural Compound as a Potential Dual Inhibitor of MDM2 and MDMX.ChemMedChem · 2025Article
- Surgery/anesthesia may cause monocytes to promote tumor development.Molecular medicine (Cambridge, Mass.) · 2025Article
- Review
- Structure and function of MDM2 and MDM4 in health and disease.The Biochemical journal · 2025Review
- Understanding and overcoming CDK4/6 inhibitor resistance in HR+/HER2- metastatic breast cancer: clinical and molecular perspectives.Therapeutic advances in medical oncology · 2025Review
- Computer-aided Drug Discovery of Epigenetic Modulators in Dual-target Therapy of Multifactorial Diseases.Current topics in medicinal chemistry · 2025Review
- Targeting MDM2-p53 interaction for breast cancer therapy.Oncology research · 2025Review
- Exploring the Chemical Features and Biomedical Relevance of Cell-Penetrating Peptides.International journal of molecular sciences · 2024Review
- Cancer-Targeting Applications of Cell-Penetrating Peptides.International journal of molecular sciences · 2024Review
- Long-Read MDM4 Sequencing Reveals Aberrant Isoform Landscape in Metastatic Melanomas.International journal of molecular sciences · 2024Article
- MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future.Pharmacological reviews · 2024Review
- Irreversible inhibition of estrogen receptor α signaling and the emergence of hormonal resistance in MCF7 breast cancer cells induced by DNA damage agents.Biomedical reports · 2024Article
- Review
- P53 together with ferroptosis: a promising strategy leaving cancer cells without escape.Acta biochimica et biophysica Sinica · 2024Article
Corrections and comments
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundMDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models.
methodsThree hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel.
resultsALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent.
conclusionThe significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.
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