ArticleMolecular cancer therapeutics2022
Small-Molecule MMRi62 Induces Ferroptosis and Inhibits Metastasis in Pancreatic Cancer via Degradation of Ferritin Heavy Chain and Mutant p53.
Article in Molecular cancer therapeutics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 69 citations in OpenAlex.
- Ferroptosis-based therapeutic strategy targeting iron metabolism and SLC7A11 overcomes oxaliplatin resistance in patient-derived pancreatic cancer organoids.Journal of experimental & clinical cancer research : CR · 2026Article
- Genetic mutations governing ferroptosis sensitivity and resistance: a precision approach to cancer therapy.Cell death & disease · 2026Review
- A fistful of iron: ferritin as a vulnerability point of the brain cancers.Cell death & disease · 2026Review
- Ferroptosis in cardiovascular diseases: molecular mechanisms and a novel therapeutic target.Molecular biomedicine · 2026Review
- Navigating the complexities of ferroptosis in pancreatic ductal adenocarcinoma: roles, mechanisms and potential applications.Cell death discovery · 2026Review
- Ferroptosis in cancer toward molecular insights and clinical translation in pancreatic cancer.Molecular cancer · 2026Review
- Exploiting metabolic cell death for cancer therapy.Nature reviews. Cancer · 2026Review
- Mechanistic Approach to Ferroptosis in Cancer and Neurological Diseases.Current drug targets · 2026Review
- Ferroptosis in cancer: metabolism, mechanisms and therapeutic prospects.Molecular cancer · 2025Review
- Review
- Focal adhesion assembly and cell migration require myoferlin in PDAC cell lines.Scientific reports · 2025Article
- NSUN2 promotes leukemogenesis by ferritin heavy chain 1-mediated anti-ferroptosis and enhancing global protein synthesis in an mClinical epigenetics · 2025Article
- Dual functionality of MDM2 in PROTACs expands the horizons of targeted protein degradation.Biomarker research · 2025Review
- Anticancer Quinolinol Small Molecules Target Multiple Pathways to Promote Cell Death and Eliminate Melanoma Cells Resistant to BRAF Inhibitors.Molecules (Basel, Switzerland) · 2025Article
- Deciphering Ferroptosis: From Molecular Pathways to Machine Learning-Guided Therapeutic Innovation.Molecular biotechnology · 2025Review
- From mechanisms to medicine: Ferroptosis as a Therapeutic target in liver disorders.Cell communication and signaling : CCS · 2025Review
- Interactions between ferroptosis and tumour development mechanisms: Implications for gynaecological cancer therapy (Review).Oncology reports · 2025Review
- Expression and prognostic value of ferritinophagy-related NCOA4 gene in low-grade glioma: integration of bioinformatics and experimental validation.BMC neurology · 2025Article
- Beyond oxidative stress: Ferroptosis as a novel orchestrator in neurodegenerative disorders.Frontiers in immunology · 2025Review
- Ursolic Acid induces ferroptosis by affecting redox balance and FADS2-mediated unsaturated fatty acid synthesis in Non-Small Cell Lung Cancer.Journal of Cancer · 2025Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
High frequency of KRAS and TP53 mutations is a unique genetic feature of pancreatic ductal adenocarcinoma (PDAC). TP53 mutation not only renders PDAC resistance to chemotherapies but also drives PDAC invasiveness. Therapies targeting activating mutant KRAS are not available and the outcomes of current PDAC treatment are extremely poor. Here, we report that MMRi62, initially identified as an MDM2-MDM4-targeting small molecule with p53-independent pro-apoptotic activity, shows anti-PDAC activity in vitro and in vivo. We show that MMRi62 inhibits proliferation, clonogenic, and spheroid growth of PDAC cells by induction of cell death. MMRi62-induced cell death in PDAC is characteristic of ferroptosis that is associated with increased autophagy, increased reactive oxygen species, and lysosomal degradation of NCOA4 and ferritin heavy chain (FTH1). In addition to induced degradation of FTH1, MMRi62 also induces proteasomal degradation of mutant p53. Interestingly, MMRi62-induced ferroptosis occurs in PDAC cell lines harboring either KRAS and TP53 double mutations or single TP53 mutation. In orthotopic xenograft PDAC mouse models, MMRi62 was capable of inhibiting tumor growth in mice associated with downregulation of NCOA4 and mutant p53 in vivo. Strikingly, MMRi62 completely abrogated metastasis of orthotopic tumors to distant organs, which is consistent with MMRi62's ability to inhibit cell migration and invasion in vitro. These findings identified MMRi62 as a novel ferroptosis inducer capable of suppressing PDAC growth and overcoming metastasis.
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