ArticleCell death discovery2020
Pevonedistat (MLN4924): mechanism of cell death induction and therapeutic potential in colorectal cancer.
Article in Cell death discovery, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 40 citations in OpenAlex.
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- MLN4924 suppresses kidney renal clear cell carcinoma progression through coordinated inhibition of Cullin1 neddylation and PSMB10-associated NF-κB inflammatory signaling.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Neddylation as a molecular integrator of metabolic dysfunction and endothelial dysfunction in type 2 diabetes.Acta pharmacologica Sinica · 2026Review
- Improved Lipophilicity Is Associated with the Cytotoxic Activity of Chlorogenic Acid Esters in In Vitro Colorectal Cancer Models.Molecules (Basel, Switzerland) · 2026Article
- The Art of Domesticating Proteins: How Cancer Cells Adapt to Therapeutic and Environmental Stressors.International journal of molecular sciences · 2026Review
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- Cellular strategies for repairing trapped protein-DNA complexes.Frontiers in pharmacology · 2026Review
- Immunoregulatory roles of post-translational modifications in colorectal cancer: mechanisms and therapeutic implications.Cellular and molecular life sciences : CMLS · 2025Review
- Neddylation inhibition induces DNA double-strand breaks, hampering tumor growth in vivo, and promotes radiosensitivity in PAX3-FOXO1 rhabdomyosarcoma.Cell death discovery · 2025Article
- RNA processing kinase inhibitors and epigenetic inhibitors in combination with oncology drugs or investigational agents in multi-cell type patient-derived tumor cell line spheroids.Cancer chemotherapy and pharmacology · 2025Article
- Neddylation status determines the therapeutic sensitivity of tyrosine kinase inhibitors in chronic myeloid leukemia.Scientific reports · 2025Article
- Comprehensive multi-omics analysis elucidates colchicine-induced toxicity mechanisms and unveils the therapeutic potential of MLN4924 and kinase inhibitors.Acta pharmacologica Sinica · 2025Article
- Lactylation modulation identifies key biomarkers and therapeutic targets in KMT2A-rearranged AML.Scientific reports · 2025Article
- Identification of EARS2 as a Potential Biomarker with Diagnostic, Prognostic, and Therapeutic Implications in Colorectal Cancer.ImmunoTargets and therapy · 2025Article
- A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo.PLoS pathogens · 2024Article
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- RBM15 Protects From Myocardial Infarction by Stabilizing NAE1.JACC. Basic to translational science · 2024Article
- Advancements in colorectal cancer research: Unveiling the cellular and molecular mechanisms of neddylation (Review).International journal of oncology · 2024Review
- Review
- Tracing back primed resistance in cancer via sister cells.Nature communications · 2024Article
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pevonedistat (MLN4924), a selective inhibitor of the NEDD8-activating enzyme E1 regulatory subunit (NAE1), has demonstrated significant therapeutic potential in several malignancies. Although multiple mechanisms-of-action have been identified, how MLN4924 induces cell death and its potential as a combinatorial agent with standard-of-care (SoC) chemotherapy in colorectal cancer (CRC) remains largely undefined. In an effort to understand MLN4924-induced cell death in CRC, we identified p53 as an important mediator of the apoptotic response to MLN4924. We also identified roles for the extrinsic (TRAIL-R2/caspase-8) and intrinsic (BAX/BAK) apoptotic pathways in mediating the apoptotic effects of MLN4924 in CRC cells, as well as a role for BID, which modulates a cross-talk between these pathways. Depletion of the anti-apoptotic protein FLIP, which we identify as a novel mediator of resistance to MLN4924, enhanced apoptosis in a p53-, TRAIL-R2/DR5-, and caspase-8-dependent manner. Notably, TRAIL-R2 was involved in potentiating the apoptotic response to MLN4924 in the absence of FLIP, in a ligand-independent manner. Moreoever, when paired with SoC chemotherapies, MLN4924 demonstrated synergy with the irinotecan metabolite SN38. The cell death induced by MLN4924/SN38 combination was dependent on activation of mitochondria through BAX/BAK, but in a p53-independent manner, an important observation given the high frequency of
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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.