Role of ER stress-driven IRE1α-XBP1 Signaling in Lung Cancer Pathogenesis

ER 应激驱动的 IRE1α-XBP1 信号在肺癌发病机制中的作用

• 批准号: 9329071
• 负责人: Michael Joseph Crowley
• 金额: $ 4.4万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329071
• 关键词: Ablation; Adjuvant Chemotherapy; CRISPR/Cas technology; Cell Line; Cell Survival; Cell physiology; Cells; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Dendritic Cells; Development; Disease Progression; Effectiveness; Endoribonucleases; Enzymes; FDA approved; Functional disorder; Genes; Genetic Models; Genetic Transcription; Goals; Human; Hypoxia; ITGAX gene; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Infiltration; Investigation; KRAS2 gene; Knock-out; Laboratories; Leukocytes; Lung Adenocarcinoma; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; Messenger RNA; Mus; Myelogenous; Non-Small-Cell Lung Carcinoma; Nucleotides; Oncogenes; Oxidative Stress; Pathogenesis; Pathway interactions; Pharmacology; Phosphotransferases; Play; Population; Pre-Clinical Model; Quality Control; RNA Interference; RNA Splicing; Recurrence; Resources; Role; Sampling; Signal Pathway; Signal Transduction; Stromal Cells; Survival Rate; System; T-Lymphocyte; TP53 gene; Therapeutic; Tissue Microarray; Transgenic Mice; Tumor Immunity; Tumor stage; XBP1 gene; arm; biological adaptation to stress; cancer cell; carcinogenesis; chemotherapy; clinically relevant; clinically significant; effective therapy; endoplasmic reticulum stress; genetic approach; genetic signature; global health; immune checkpoint blockade; in vivo; inhibitor/antagonist; insight; mutant; nanoparticle; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutic intervention; nutrient deprivation; outcome forecast; prognostic; protein folding; recombinase; small molecule inhibitor; success; targeted treatment; therapeutic target; therapy development; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis

Abstract Mutant KRAS driven non-small cell lung cancer (NSCLC), confer a dismal 5-year survival rate of only 15-20%. Despite this clinical significance, there is a lack of an effective targeted therapy for the treatment of KRAS lung cancer. Given this unmet clinical need, my goal is to investigate the endoplasmic reticulum (ER) stress response, particularly the protumorigenic IRE1α-XBP1 signaling pathway as an untapped resource of novel targets for therapy development. The protumorigenic role of ER stress response is being explored in various tumor types. However, this pathway had not been investigated properly in lung cancer. To first establish the clinical relevance, I analyzed a tissue microarray of >300 NSCLC clinical samples, and showed activated XBP1 in both the cancer and the stromal cells. Consistent with these observations, XBP-1 activation was observed in both the cancer cells and in the intratumoral dendritic cells, associated with activation of downstream genes in mutant Kras, p53-/- preclinical model of lung cancer. These preliminary findings, have led to the hypothesis that the aberrant IRE1α- XBP1signaling axis may contribute to carcinogenesis. Using genetic approaches (CRISPR/RNAi), and compartment-restricted recombinase systems (Clec9a-Cre or CD11c-Cre), I will investigate the cell-specific roles of IRE1α-XBP1 signaling in tumor growth, metastatic capacity and survival. Perturbation of IRE1α/XBP-1 in tumor-infiltrating DCs will be used to assess their role in T-cell-mediated anti-tumor immunity, as this may provide key insights into whether XBP-1 targeting would enhance the efficacy of immune checkpoint blockade inhibitors. Finally, the therapeutic potential of targeting the IRE-1-XBP1 pathway in NSCLC will be accomplished using selective pharmacological inhibitors of IRE1α. This study has a potential to yield targets of prognostic and therapeutic value in the IRE-1-XBP1 pathway in KRAS lung cancer, which represents >30% of lung adenocarcinomas.

摘要 突变KRAS驱动的非小细胞肺癌（NSCLC），5年生存率为 只有15- 20%。尽管有这种临床意义，但缺乏有效的靶向治疗。 KRAS肺癌的治疗鉴于这种未满足的临床需求，我的目标是调查 内质网（ER）应激反应，特别是促肿瘤性IRE 1 α-XBP 1 信号通路作为治疗开发的新靶点的未开发资源。的 ER应激反应的促肿瘤发生作用正在各种肿瘤类型中被探索。然而，在这方面， 这一途径在肺癌中尚未得到适当的研究。首先建立临床 相关性，我分析了>300个NSCLC临床样本的组织微阵列，并显示 在癌细胞和基质细胞中都激活了XBP 1。与这些观察相一致， 在癌细胞和肿瘤内树突状细胞中均观察到XBP-1活化， 与突变型Kras、p53-/-肺临床前模型中下游基因的激活相关 癌这些初步的发现，导致了一个假设，即异常的IRE 1 α- XBP 1信号轴可能参与了肿瘤的发生。使用遗传学方法 （CRISPR/RNAi）和区室限制性重组酶系统（Clec 9a-Cre或CD 11 c-Cre）， 我将研究IRE 1 α-XBP 1信号传导在肿瘤生长、转移和转移中的细胞特异性作用。 能力和生存。干扰肿瘤浸润DC中的IRE 1 α/XBP-1将用于 评估它们在T细胞介导的抗肿瘤免疫中的作用，因为这可能提供关键的见解， XBP-1靶向是否会增强免疫检查点阻断抑制剂的功效。 最后，靶向IRE-1-XBP 1通路在NSCLC中的治疗潜力将是 使用IRE 1 α的选择性药理学抑制剂完成。这项研究有可能 产生KRAS肺中IRE-1-XBP 1通路中具有预后和治疗价值的靶点 肺癌，占肺腺癌的>30%。