美国德克萨斯大学MD安德森癌症中心Shiaw-Yih Lin、Nidhi Sahni、Daniel J. McGrail等研究人员合作发现，蛋白质组不稳定性是错配修复缺陷型癌症的治疗弱点。相关论文于2020年2月27日在线发表在国际学术期刊《癌细胞》上。

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

Author: Daniel J. McGrail, Jeannine Garnett, Jun Yin, Hui Dai, David J.H. Shih, Truong Nguyen Anh Lam, Yang Li, Chaoyang Sun, Yongsheng Li, Rosemarie Schmandt, Ji Yuan Wu, Limei Hu, Yulong Liang, Guang Peng, Eric Jonasch, David Menter, Melinda S. Yates, Scott Kopetz, Karen H. Lu, Russell Broaddus, Gordon B. Mills, Nidhi Sahni, Shiaw-Yih Lin

Issue&Volume: 2020-02-27

Abstract: Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype that can leadto tumorigenesis; however, the functional impact of the high mutation burden resultingfrom this phenotype remains poorly explored. Here, we demonstrate that dMMR-induceddestabilizing mutations lead to proteome instability in dMMR tumors, resulting inan abundance of misfolded protein aggregates. To compensate, dMMR cells utilize aNedd8-mediated degradation pathway to facilitate clearance of misfolded proteins.Blockade of this Nedd8 clearance pathway with MLN4924 causes accumulation of misfoldedprotein aggregates, ultimately inducing immunogenic cell death in dMMR cancer cells.To leverage this immunogenic cell death, we combined MLN4924 treatment with PD1 inhibitionand found the combination was synergistic, significantly improving efficacy over eithertreatment alone.

DOI: 10.1016/j.ccell.2020.01.011

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30050-7