The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer.. The integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer.

The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes specific translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a novel therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a novel rationale for the implementation of ISR-based regimens in LUAD treatment. Overall design: RNA seq of eIF2αS/S and eIF2αA/A KRAS G12D Tumor Cells

整合应激反应（integrated stress response, ISR）是一类至关重要的应激支持通路，如今愈发被认定为肿瘤发生的决定性因素。本研究证实，整合应激反应在肺腺癌（lung adenocarcinoma, LUAD）的发生发展中发挥关键作用——肺腺癌是肺癌最常见的组织学类型，也是全球范围内癌症死亡的首要诱因。在928例肺腺癌患者队列中，作为整合应激通路核心枢纽的翻译起始因子eIF2（eukaryotic translation initiation factor 2, eIF2）的磷酸化形式p-eIF2α水平升高，该现象与肿瘤侵袭性增强、增殖能力提升及不良预后密切相关。本研究在小鼠KRAS驱动的肺肿瘤发生模型中解析整合应激反应的作用机制，结果显示p-eIF2α可特异性抑制双特异性磷酸酶6（dual specificity phosphatase 6, DUSP6）的翻译过程，进而导致细胞外调节蛋白激酶（extracellular signal-regulated kinase, ERK）的磷酸化形式p-ERK水平升高。采用整合应激反应抑制剂进行干预，包括一款毒性有限的记忆增强药物，可为KRAS驱动的肺癌提供全新治疗选择，因其可显著抑制肿瘤生长并延长小鼠生存期。本研究数据为在肺腺癌治疗中应用基于整合应激反应的治疗方案提供了全新的理论依据。实验设计概述：对eIF2αS/S及eIF2αA/A型KRAS G12D肿瘤细胞进行RNA测序（RNA-seq）。