| Literature DB >> 32109374 |
Daniel J McGrail1, Jeannine Garnett2, Jun Yin2, Hui Dai2, David J H Shih2, Truong Nguyen Anh Lam3, Yang Li2, Chaoyang Sun2, Yongsheng Li2, Rosemarie Schmandt4, Ji Yuan Wu5, Limei Hu2, Yulong Liang2, Guang Peng6, Eric Jonasch3, David Menter5, Melinda S Yates4, Scott Kopetz5, Karen H Lu4, Russell Broaddus7, Gordon B Mills8, Nidhi Sahni9, Shiaw-Yih Lin10.
Abstract
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.Entities:
Keywords: colorectal cancer (COAD); endometrial cancer (UCEC); immunotherapy; microsatellite instability (MSI); mismatch repair (MMR); neddylation; protein degredation; protein homeostasis
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Year: 2020 PMID： 32109374 PMCID： PMC7337255 DOI： 10.1016/j.ccell.2020.01.011
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743