pevonedistat and Endometrial-Neoplasms

To explore the neddylation pathway, found to be highly activated in various cancers, as a potential therapeutic target in endometrial carcinoma, one of the three most frequent malignant tumours in the female reproductive system.. Data from The Cancer Genome Atlas were analysed using online servers. Expression levels of key neddylation genes were validated by reverse-transcription polymerase chain reaction and western blots of tumour and adjacent tissues. Underlying mechanisms and the effects on cell activities of the neddylation pathway-specific inhibitor, MLN4924, were investigated in endometrial cancer cell lines.. Key neddylation enzymes, ubiquitin conjugating enzyme E2 M (. The neddylation pathway was identified to play an important role in endometrial cancer. The neddylation specific inhibitor, MLN4924, may be a potential therapeutic drug for endometrial carcinoma.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclopentanes; Endometrial Neoplasms; Female; Humans; NEDD8 Protein; Pyrimidines; Ubiquitins

Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype that can lead to tumorigenesis; however, the functional impact of the high mutation burden resulting from this phenotype remains poorly explored. Here, we demonstrate that dMMR-induced destabilizing mutations lead to proteome instability in dMMR tumors, resulting in an abundance of misfolded protein aggregates. To compensate, dMMR cells utilize a Nedd8-mediated degradation pathway to facilitate clearance of misfolded proteins. Blockade of this Nedd8 clearance pathway with MLN4924 causes accumulation of misfolded protein aggregates, ultimately inducing immunogenic cell death in dMMR cancer cells. To leverage this immunogenic cell death, we combined MLN4924 treatment with PD1 inhibition and found the combination was synergistic, significantly improving efficacy over either treatment alone.

Topics: Animals; Cell Line, Tumor; Colorectal Neoplasms; Cyclopentanes; DNA Mismatch Repair; Endometrial Neoplasms; Female; HCT116 Cells; Humans; Immunotherapy; Mice, Inbred C57BL; Mice, Transgenic; Microsatellite Instability; Mutation; NEDD8 Protein; Programmed Cell Death 1 Receptor; Protein Stability; Proteome; Pyrimidines; Xenograft Model Antitumor Assays