Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
Science. 2023 Sep 8;381(6662):eabn4180. doi: 10.1126/science.abn4180.
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.
尽管在靶向突变 KRAS 方面取得了重大进展，但肿瘤对 KRAS 抑制剂（KRASi）的耐药性仍然是进展的主要障碍。在这里，我们报告蛋白质稳态重编程是多种 KRASi 耐药机制的关键汇聚点。致癌 KRAS 的失活下调了热休克反应和未折叠蛋白反应的肌醇需求酶 1α（IRE1α）分支，导致严重的蛋白质稳态紊乱。然而，获得性 KRASi 耐药肿瘤中，IRE1α 以 ER 应激独立的方式选择性重新激活，从而恢复蛋白质稳态。致癌 KRAS 通过细胞外信号调节激酶（ERK）依赖性 IRE1α 磷酸化促进 IRE1α 蛋白稳定性，导致 IRE1α 与 3-羟基-3-甲基戊二酰基辅酶 A 还原酶降解（HRD1）E3 连接酶分离。在 KRASi 耐药肿瘤中，重新激活的 ERK 和过度激活的 AKT 恢复了 IRE1α 的磷酸化和稳定性。抑制 IRE1α 克服了对 KRASi 的耐药性。这项研究揭示了一种可药物治疗的机制，导致蛋白质稳态重编程并促进 KRASi 耐药性。
