ER stress-driven IRE1a-XBP1 signaling in lung cancer

肺癌中内质网应激驱动的 IRE1a-XBP1 信号传导

• 批准号: 10587002
• 负责人: Juan R Cubillos-Ruiz
• 金额: $ 66.35万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587002
• 关键词: Binding Proteins; Breast; Cancer Model; Cancer Patient; Clinical; Clinical Trials; Code; Endoplasmic Reticulum; FDA approved; Free Radicals; Future; Genetic; Goals; Human; Hypoxia; Immune Evasion; Immunosuppression; Immunotherapeutic agent; Interferons; Lymphoid Cell; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Messenger RNA; Mus; Myeloid Cells; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Nutrient; Outcome; Ovarian; Pathway interactions; Patients; Poly(ADP-ribose) Polymerase Inhibitor; Prediction of Response to Therapy; Protein Isoforms; Proteins; Radiation therapy; Repression; Ribonucleases; Role; STING agonists; Signal Transduction; Starvation; Testing; Therapeutic; Time; Treatment outcome; Tumor Promotion; XBP1 gene; antitumor effect; arm; biological adaptation to stress; cancer cell; cancer type; checkpoint inhibition; clinical translation; clinically relevant; cohort; design; effective therapy; endoplasmic reticulum stress; genetic approach; genetic signature; immunoregulation; inhibitor; innovation; insight; intervention effect; melanoma; molecular targeted therapies; mortality; mouse model; multitask; next generation; novel; novel therapeutic intervention; outcome prediction; pharmacologic; predictive signature; programs; protein folding; response; sensor; survival outcome; survival prediction; therapeutic target; transcription factor; transcriptome sequencing; translational potential; tumor growth; tumor microenvironment; tumor progression

Abstract FDA approved molecularly targeted therapies have not significantly reduced mortality in non-small cell lung cancer (NSCLC) patients. Therefore, identification and characterization of novel targets for developing effective therapies is warranted. In this proposal, we will develop endoplasmic reticulum (ER) sensor IRE1 as a potential therapeutic target in NSCLC. Adverse conditions in the tumor microenvironment (TME) can rapidly disrupt the protein folding capacity of the ER, thereby triggering a state of cellular “ER stress”. The ER stress response arm of the unfolded protein response, particularly the conserved IRE1-XBP1 pathway has emerged as a central orchestrator of malignant progression. Activated during periods of ER stress, the IRE1 RNAse domain cleaves its downstream target X-box binding protein (Xbp1) mRNA (inactive, XBP1u), converting it to active isoform (XBP1s), which serves as a functionally active transcription factor. We have determined that increased expression of XBP1s is associated with poor survival in NSCLC, cancer cell-intrinsic deletion of IRE1 delayed malignant progression and extended survival in mouse models of NSCLC. IRE1 deficiency triggered protective type-I IFN responses associated with marked reprogramming of both the lymphoid and myeloid cell subsets. These findings have led to the hypothesis that dysregulated IRE1-XBP1s signaling in cancer cells facilitates NSCLC progression by governing key immunomodulatory programs in the tumor microenvironment (TME). Therefore, understanding the underlying mechanisms has the potential to generate unique therapeutic strategies against difficult to treat NSCLC. We will determine mechanisms by which persistent activation of ER stress sensor IRE1 drives immunosuppression in the TME (Aim 1), determine if pharmacological inhibition of IRE1α sensitizes NSCLC to PARP inhibitors, and STING agonists by enhancing type-I IFN responses (Aim 2), and assess the clinical relevance of a novel IRE1 gene signature in predicting treatment outcomes in human NSCLC (Aim 3). This proposal is conceptually and technically innovative as it seeks to investigate for the first time how cancer cell-intrinsic IRE1α activation drives immunosuppression in the TME that facilitates immune evasion by disrupting cDC1 function and blunting type-I IFN responses. We expect that the mechanistic insights from these studies will generate unique translational opportunities that may lead to the design of future clinical trials with clinical grade IRE1 inhibitors.

摘要 FDA批准的分子靶向治疗并没有显著降低非小细胞肺癌的死亡率。 细胞肺癌（NSCLC）患者。因此，新靶点的识别和表征 开发有效的治疗方法是必要的。在这个建议中，我们将开发内质网 内质网（ER）传感器IRE 1可作为NSCLC的潜在治疗靶点。不利条件 肿瘤微环境（TME）可迅速破坏ER的蛋白质折叠能力， 从而触发细胞“ER应激”状态。展开的ER应激反应臂 蛋白质反应，特别是保守的IRE 1 β-XBP 1途径已经成为一个中心的 恶性进展的协调者在内质网应激期间被激活，IRE 1 β RNA酶 结构域切割其下游靶X-box结合蛋白（Xbp 1）mRNA（无活性，XBP 1u）， 将其转化为活性同种型（XBP 1 s），其作为功能活性转录因子。 我们已经确定，XBP 1 s表达增加与胃癌患者的生存率低有关。 NSCLC，癌细胞固有的IRE 1缺失可延迟恶性进展并延长 NSCLC小鼠模型中的存活率。IRE 1 β缺陷引发I型IFN保护性应答 与淋巴细胞和骨髓细胞亚群的显著重编程相关。这些 这些发现导致了一种假设，即癌细胞中IRE 1 β-XBP 1信号转导失调 通过控制肿瘤中的关键免疫调节程序促进NSCLC进展 微环境（TME）。因此，了解潜在的机制有可能 针对难以治疗的NSCLC制定独特的治疗策略。 我们将确定ER应力传感器IRE 1持续激活的机制， TME中的免疫抑制（目的1），确定IRE 1 α的药理学抑制作用 通过增强I型IFN应答使NSCLC对PARP抑制剂和STING激动剂敏感 (Aim 2），并评估一种新的IRE 1 β基因标签在预测治疗中的临床相关性。 人NSCLC的结局（目标3）。该提案在概念和技术上都具有创新性， 试图首次研究癌细胞内在的IRE 1 α激活如何驱动 TME中的免疫抑制，通过破坏cDC 1功能促进免疫逃避， 减弱I型干扰素反应我们希望这些研究的机械见解将 产生独特的转化机会，可能导致未来临床试验的设计， 临床级IRE 1 β抑制剂。