2. Academic Validation
  3. Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer

Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer

  • Cancer Cell. 2020 Mar 16;37(3):371-386.e12. doi: 10.1016/j.ccell.2020.01.011.
Daniel J McGrail 1,  Jeannine Garnett 2,  Jun Yin 2,  Hui Dai 2,  David J H Shih 2,  Truong Nguyen Anh Lam 3,  Yang Li 2,  Chaoyang Sun 2,  Yongsheng Li 2,  Rosemarie Schmandt 4,  Ji Yuan Wu 5,  Limei Hu 2,  Yulong Liang 2,  Guang Peng 6,  Eric Jonasch 3,  David Menter 5,  Melinda S Yates 4,  Scott Kopetz 5,  Karen H Lu 4,  Russell Broaddus 7,  Gordon B Mills 8,  Nidhi Sahni 9,  Shiaw-Yih Lin 10
Affiliations

Affiliations

  • 1 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: djmcgrail@mdanderson.org.
  • 2 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 3 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 4 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 5 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 6 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 7 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
  • 8 Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
  • 9 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Program in Quantitative and Computational Biosciences (QCB), Baylor College of Medicine, Houston, TX 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: nsahni@mdanderson.org.
  • 10 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: sylin@mdanderson.org.
PMID: 32109374 DOI: 10.1016/j.ccell.2020.01.011
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.

Keywords

colorectal cancer (COAD); endometrial cancer (UCEC); immunotherapy; microsatellite instability (MSI); mismatch repair (MMR); neddylation; protein degredation; protein homeostasis.

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