ArticleCancer cell2020
Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer.
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Article in Cancer cell, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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72citing papers in PubMed
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72 citing papers in PubMed, 110 citations in OpenAlex.
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- Targeting cancer-intrinsic protein neddylation bypasses the loss of JAK/STAT signaling and overcomes acquired resistance to immunotherapy.Research square · 2026Article
- A multi-level charged micelle-based microneedle transdermal system for immunosuppressive tumor microenvironment regulation and synergistic therapy.Materials today. Bio · 2026Article
- Neddylation: from regulatory mechanisms to clinical implications in cancer.Journal of advanced research · 2026Review
- A DR5/Ligase 3-mediated feedback loop perpetuates immunogenicity in mismatch repair deficient colorectal cancer.Gastroenterology · 2026Article
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- Decoding neddylation in malignancies: molecular mechanisms, biological functions, therapeutic resistance, and clinical potential.Cell death & disease · 2026Review
- The role of neddylation in colorectal cancer and its therapeutic potential.Discover oncology · 2025Review
- Nonrepair functions of DNA mismatch repair proteins: new avenues for precision oncology.Trends in cancer · 2025Review
- The ubiquitin ligase RCBTB2 regulates aggrephagy and inhibits prostate cancer progression by targeting GPAA1 for degradation.American journal of cancer research · 2025Article
- Current trends in sensitizing immune checkpoint inhibitors for cancer treatment.Molecular cancer · 2024Review
- The Role of Endoplasmic Reticulum Stress on Reducing Recombinant Protein Production in Mammalian Cells.Biochemical engineering journal · 2024Article
- ER-associated degradation ligase HRD1 links ER stress to DNA damage repair by modulating the activity of DNA-PKcs.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Potent therapeutic strategy in gastric cancer with microsatellite instability-high and/or deficient mismatch repair.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2024Review
- Detecting microsatellite instability by length comparison of microsatellites in the 3' untranslated region with RNA-seq.Briefings in bioinformatics · 2024Article
- Senataxin deficiency disrupts proteostasis through nucleolar ncRNA-driven protein aggregation.The Journal of cell biology · 2024Article
- The Double-Edged Effects of MLN4924: Rethinking Anti-Cancer Drugs Targeting the Neddylation Pathway.Biomolecules · 2024Review
- Oncogenic and immunological role of EDIL3 in human tumours: From pan-cancer analysis to validation in gastric cancer.Heliyon · 2024Article
- Article
12 more citing papers are in PubMed but not listed here.
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Authors and funding
23 authors at 3 institutions in 1 country.
Daniel J McGrailDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: djmcgrail@mdanderson.org.
Jeannine GarnettDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jun YinDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hui DaiDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
David J H ShihDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Truong Nguyen Anh LamDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Yang LiDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chaoyang SunDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Yongsheng LiDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Rosemarie SchmandtDepartment of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Ji Yuan WuDepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Limei HuDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Yulong LiangDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Guang PengDepartment of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Eric JonaschDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
David MenterDepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Melinda S YatesDepartment of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Scott KopetzDepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Karen H LuDepartment of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Russell BroaddusDepartment of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
Gordon B MillsKnight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
Nidhi SahniDepartment 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.
Shiaw-Yih LinDepartment of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: sylin@mdanderson.org.
The University of Texas MD Anderson Cancer Center · USOregon Health & Science University · USUniversity of North Carolina at Chapel Hill · US
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Scott Kopetz · 1985 to 2026
$290.8MTargeting the PI3K Signaling Pathway in Endometrial CarcinomaP50CA098258 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI BODURKA, DIANE · 2003 to 2020
$32.0MCenter for Clinical and Translational Sciences (CCTS)KL2TR000370 · NCATS · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI MCPHERSON, DAVID D · 2012 to 2016
$4.3MIntegrative bioinformatics and functional characterization of oncogenic driver aberrations in cancerU01CA217842 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI DENEEN, BENJAMIN, MILLS, GORDON B. · 2017 to 2021
$3.6MSignature-guided therapy for mismatch repair defective cancersR01CA218287 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI LIN, SHIAW-YIH · 2017 to 2021
$1.9MMolecular Mechanisms Underlying Environmental Effects that Influence Penetrance in Lynch Syndrome-Associated Endometrial CancerR01CA216103 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI YATES, MELINDA S. · 2017 to 2021
$1.4MTraining Grant in Cancer BiologyT32CA186892 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KALLURI, RAGHU · 2016 to 2020
$1.1MNCATS NIH HHS KL2 TR000370NCI NIH HHS P30 CA016672NCI NIH HHS P50 CA098258NCI NIH HHS R01 CA216103NCI NIH HHS R01 CA218287NCI NIH HHS T32 CA186892NCI NIH HHS U01 CA217842
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.
Indexed as
DNA Mismatch RepairAnimalsCell Line, TumorColorectal NeoplasmsCyclopentanesEndometrial NeoplasmsFemaleHCT116 CellsHumansImmunotherapyMice, Inbred C57BLMice, TransgenicMicrosatellite InstabilityMutationNEDD8 ProteinProgrammed Cell Death 1 ReceptorCyclopentanesNEDD8 ProteinNEDD8 protein, humanPDCD1 protein, humanpevonedistatProgrammed Cell Death 1 ReceptorProteomePyrimidinescolorectal cancer (COAD)endometrial cancer (UCEC)immunotherapymicrosatellite instability (MSI)mismatch repair (MMR)neddylationprotein degredationprotein homeostasis
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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.