Related Experiment Video
Updated: Dec 27, 2025
Identifying DNA Mutations in Purified Hematopoietic Stem/Progenitor Cells
Published on: February 24, 2014
Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer
Daniel J McGrail1, Jeannine Garnett1, Jun Yin1
1Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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.
Insights
Deficient DNA mismatch repair (dMMR) causes proteome instability and protein buildup in tumors. Blocking a specific protein clearance pathway with MLN4924 triggers cancer cell death, enhancing immunotherapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Immunology
Background:
- Deficient DNA mismatch repair (dMMR) leads to a hypermutator phenotype and tumorigenesis.
- The functional consequences of high mutation burden in dMMR tumors are not well understood.
- Misfolded protein aggregates are a hallmark of dMMR tumors.
Purpose of the Study:
- To investigate the impact of dMMR-induced mutations on proteome stability.
- To explore the role of Nedd8-mediated degradation in dMMR cancer cells.
- To evaluate the therapeutic potential of blocking Nedd8 clearance in combination with PD1 inhibition.
Main Methods:
- Analysis of proteome instability in dMMR tumors.
- Investigating the Nedd8-mediated protein degradation pathway.
- Treatment of dMMR cancer cells with MLN4924 and PD1 inhibitors.
Main Results:
- dMMR-induced mutations result in proteome instability and accumulation of misfolded protein aggregates.
- dMMR cells rely on Nedd8-mediated degradation for clearance of these aggregates.
- MLN4924 treatment blocks Nedd8 clearance, leading to aggregate accumulation and immunogenic cell death.
- Combination therapy of MLN4924 and PD1 inhibition demonstrated synergistic efficacy.
Conclusions:
- Proteome instability is a key consequence of dMMR.
- Targeting the Nedd8 clearance pathway offers a novel therapeutic strategy for dMMR cancers.
- Combination of MLN4924 and PD1 inhibition shows promise for enhancing anti-tumor immunity.
More Related Videos
Related Concept Videos
01:20Mismatch Repair
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
01:36Mismatch Repair
01:38Nucleotide Excision Repair
Cells are regularly exposed to mutagens—factors in the environment that can damage DNA and generate mutations. UV radiation is one of the most common mutagens and is estimated to introduce a significant number of changes in DNA. These include bends or kinks in the structure, which can block DNA replication or transcription. If these errors are not fixed, the damage can cause mutations, which in turn can result in cancer or disease depending on which sequences are...
01:08Nucleotide Excision Repair
02:56Treatment Resistant Cancers
02:23Abnormal Proliferation