Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer
Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer
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DOI：
10.1016/j.ccell.2020.01.011
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发表时间：
2020-03-16
期刊：
影响因子：
50.3
通讯作者：
Lin, Shiaw-Yih
中科院分区：
文献类型：
--
作者：
McGrail, Daniel J.;Garnett, Jeannine;Lin, Shiaw-Yih
DNA错配修复缺陷（dMMR）诱导的超变表型，可导致肿瘤发生，然而，这种表型导致的高突变负荷的功能影响仍然很少探索。在这里，我们证明了dMMR诱导的不稳定突变导致dMMR肿瘤中蛋白质组的不稳定，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的清除。MLN 4924阻断该Nedd8清除途径导致错误折叠蛋白聚集体蓄积，最终诱导dMMR癌细胞中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，与单独治疗相比显著改善了疗效。
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.