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

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Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer.
Cancer Cell ( IF 48.8 ) Pub Date : 2020-02-27 , DOI: 10.1016/j.ccell.2020.01.011
Daniel J McGrail ₁ , Jeannine Garnett ₁ , Jun Yin ₁ , Hui Dai ₁ , David J H Shih ₁ , Truong Nguyen Anh Lam ₂ , Yang Li ₁ , Chaoyang Sun ₁ , Yongsheng Li ₁ , Rosemarie Schmandt ₃ , Ji Yuan Wu ₄ , Limei Hu ₁ , Yulong Liang ₁ , Guang Peng ₅ , Eric Jonasch ₂ , David Menter ₄ , Melinda S Yates ₃ , Scott Kopetz ₄ , Karen H Lu ₃ , Russell Broaddus ₆ , Gordon B Mills ₇ , Nidhi Sahni ₈ , Shiaw-Yih Lin ₁

Affiliation

Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
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.

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.

中文翻译：

蛋白质组不稳定性是错配修复缺陷癌症的治疗漏洞。

DNA错配修复缺陷（dMMR）会诱导超变表型，从而导致肿瘤发生；然而，这种表型引起的高突变负担的功能影响仍然很少被探索。在这里，我们证明 dMMR 诱导的不稳定突变会导致 dMMR 肿瘤中蛋白质组不稳定，从而导致大量错误折叠的蛋白质聚集体。为了补偿，dMMR 细胞利用 Nedd8 介导的降解途径来促进错误折叠蛋白质的清除。用 MLN4924 阻断 Nedd8 清除途径会导致错误折叠蛋白聚集体的积累，最终诱导 dMMR 癌细胞的免疫原性细胞死亡。为了利用这种免疫原性细胞死亡，我们将 MLN4924 治疗与 PD1 抑制相结合，发现该组合具有协同作用，比单独治疗中的任何一种治疗都显着提高了疗效。

更新日期：2020-02-28

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