研究人员报告了蛋白稳态重编程是多种KRAS抗性机制的关键汇聚点。致癌KRAS失活会下调热休克反应和未折叠蛋白反应的肌醇需求酶1α（IRE1α）分支，导致严重的蛋白稳态紊乱。然而，在获得性KRAS耐药肿瘤中，IRE1α以一种与ER应激无关的方式被选择性地重新激活，从而恢复了蛋白稳态。致癌的KRAS通过细胞外信号调节激酶（ERK）依赖的IRE1α磷酸化促进了IRE1α蛋白的稳定性，导致IRE1α与3-羟基-3-甲基戊二酰还原酶降解（HRD1）E3连接酶脱离。
在KRAS抗性肿瘤中，重新激活的ERK和过度激活的AKT都能恢复IRE1α的磷酸化和稳定性。抑制IRE1α可克服对KRAS抑制剂（KRASi）的耐药性。这项研究揭示了一种导致蛋白稳态重编程和促进KRASi耐药性的药物机制。
据悉，尽管在靶向突变型KRAS方面取得了重大进展，但肿瘤对KRASi的耐药性仍然是取得进展的主要障碍。
附：英文原文
Title: Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors
Author: Xiangdong Lv, Xuan Lu, Jin Cao, Qin Luo, Yao Ding, Fanglue Peng, Apar Pataer, Dong Lu, Dong Han, Eric Malmberg, Doug W. Chan, Xiaoran Wang, Sara R. Savage, Sufeng Mao, Jingjing Yu, Fei Peng, Liang Yan, Huan Meng, Laure Maneix, Yumin Han, Yiwen Chen, Wantong Yao, Eric C. Chang, Andre Catic, Xia Lin, George Miles, Pengxiang Huang, Zheng Sun, Bryan Burt, Huamin Wang, Jin Wang, Qizhi Cathy Yao, Bing Zhang, Jack A. Roth, Bert W. O’Malley, Matthew J. Ellis, Mothaffar F. Rimawi, Haoqiang Ying, Xi Chen
Issue&Volume: 2023-09-08
Abstract: Despite substantial advances in targeting mutant KRAS, tumor resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report proteostasis reprogramming as a key convergence point of multiple KRASi-resistance mechanisms. Inactivation of oncogenic KRAS down-regulated both the heat shock response and the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response, causing severe proteostasis disturbances. However, IRE1α was selectively reactivated in an ER stress–independent manner in acquired KRASi-resistant tumors, restoring proteostasis. Oncogenic KRAS promoted IRE1α protein stability through extracellular signal–regulated kinase (ERK)–dependent phosphorylation of IRE1α, leading to IRE1α disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase. In KRASi-resistant tumors, both reactivated ERK and hyperactivated AKT restored IRE1α phosphorylation and stability. Suppression of IRE1α overcame resistance to KRASi. This study reveals a druggable mechanism that leads to proteostasis reprogramming and facilitates KRASi resistance.
DOI: abn4180
Source: https://www.science.org/doi/full/10.1126/science.abn4180