OST Inhibition in NSCLC

NSCLC 中的 OST 抑制

• 批准号: 10170299
• 负责人: Joseph N. Contessa
• 金额: $ 48.8万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10170299
• 关键词: Address; Animal Model; Apoptosis; Asparagine; Biological Models; Bypass; Catalytic Domain; Cell Cycle Arrest; Cell Proliferation; Cell Surface Proteins; Cell Survival; Cells; Chemicals; Clinic; Clinical Trials; Combined Modality Therapy; Complex; Coupled; Couples; Data; Diagnosis; Disease; Drug Kinetics; Endoplasmic Reticulum; Epidermal Growth Factor Receptor; FGFR1 gene; Fluorescence; Gene Amplification; Glycoproteins; Goals; Immune; Immune checkpoint inhibitor; In Vitro; Individual; KRAS2 gene; Lead; Link; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Membrane Glycoproteins; Modality; Molecular; Morbidity - disease rate; Morphology; Mutation; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Oncogenic; Pathway interactions; Patient-Focused Outcomes; Pharmaceutical Chemistry; Pharmacology; Polysaccharides; Post-Translational Protein Processing; Prevention; Process; Property; Protein Complex Subunit; Protein Overexpression; Proteins; Radiation Tolerance; Radiation therapy; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Research; Resistance; Series; Signal Pathway; Signal Transduction; Site; Specificity; Structure; Subgroup; Systemic Therapy; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Translating; Translations; Treatment Efficacy; Tyrosine Kinase Inhibitor; United States; Work; analog; base; cancer subtypes; cancer survival; cancer therapy; cell killing; clinical translation; combinatorial; design; drug development; drug discovery; drug sensitivity; efficacy testing; epithelial to mesenchymal transition; experimental study; gene product; glycosylation; high throughput screening; immune checkpoint; improved; in vivo; in vivo evaluation; inhibitor/antagonist; lung cancer cell; mortality; mutant; neoplastic cell; novel; novel strategies; novel therapeutics; overexpression; programs; receptor; senescence; small molecule; small molecule inhibitor; therapeutic development; therapy resistant; treatment strategy; tumor; tumor growth; tumor xenograft

Non-small cell lung cancers (NSCLC) are aggressive tumors that are a major cause of morbidity and mortality in the United States. In the past decade, the introduction of systemic therapies such as receptor tyrosine kinase targeted inhibitors and immune checkpoint inhibitors have significantly improved patient outcomes. However, therapeutic resistance to these therapies frequently develops and is characterized by parallel signaling through other co-expressed receptor glycoproteins. We have therefore investigated the feasibility of disrupting asparagine (N) linked glycosylation, a co- and post-translational protein modification, as a strategy to block both primary and bypass glycoprotein survival signaling in NSCLC. Although this pathway is target rich and involves at least 34 gene products, pharmacologic inhibitors that regulate this process have not previously been available. We have identified a first in class small molecule inhibitor of the oligosaccharyltransferase (OST), the multi-subunit enzymatic complex that transfers glycans to elongating proteins in the endoplasmic reticulum. This inhibitor reduces OST fidelity by targeting the catalytic subunit and results in a site-specific and partial inhibition of glycosylation. In NSCLC with activation of RTK dependent oncogenic signaling, OST inhibition blocks tumor cell proliferation and couples favorably with TKIs to enhance apoptosis and xenograft tumor growth. We now propose to characterize and advance novel small molecule inhibitors of the OST with respect to catalytic subunit inhibition and effects on EGFR driven NSCLC. Because glycoprotein bypass signaling is also operative in NSCLC subtypes with FGFR1 amplification or KRAS mutation, we will define the signaling mechanisms and determine the sensitivity of these tumors to OST inhibition. This project will also investigate the effects of OST inhibition on NSCLC radiosensitivity and identify how glycoprotein dependent cellular programs mediate intrinsic and immune mediated therapeutic resistance. Together this work will advance OST inhibition as a novel treatment strategy for NSCLC with the potential of delivering an OST inhibitor that can be translated to the clinic.

非小细胞肺癌 (NSCLC) 是侵袭性肿瘤，是发病率和死亡率的主要原因 在美国。在过去的十年中，受体酪氨酸等系统疗法的引入 激酶靶向抑制剂和免疫检查点抑制剂显着改善了患者的治疗效果。 然而，对这些疗法的治疗耐药性经常出现，其特点是平行 通过其他共表达受体糖蛋白发出信号。因此我们研究了可行性 破坏天冬酰胺 (N) 连接的糖基化（一种共翻译和翻译后蛋白质修饰）作为一种策略 阻断 NSCLC 中的主要和旁路糖蛋白生存信号传导。虽然这条途径是目标 丰富且涉及至少34种基因产物，调节这一过程的药物抑制剂尚未发现 以前可用。我们已经发现了一种一流的小分子抑制剂 寡糖转移酶 (OST)，一种多亚基酶复合物，可将聚糖转移至延伸 内质网中的蛋白质。该抑制剂通过靶向催化亚基来降低 OST 保真度 导致糖基化的位点特异性和部分抑制。在具有 RTK 依赖性激活的 NSCLC 中 致癌信号传导、OST 抑制可阻止肿瘤细胞增殖并与 TKI 有利地结合以增强 细胞凋亡和异种移植肿瘤生长。我们现在建议表征和推进新型小分子 OST 抑制剂对催化亚基抑制和对 EGFR 驱动的 NSCLC 的影响。因为 糖蛋白旁路信号传导在 FGFR1 扩增或 KRAS 的 NSCLC 亚型中也有效 突变，我们将定义信号传导机制并确定这些肿瘤对 OST 的敏感性 抑制。该项目还将研究 OST 抑制对 NSCLC 放射敏感性的影响并确定 糖蛋白依赖性细胞程序如何介导内在和免疫介导的治疗耐药性。 这项工作将共同推进 OST 抑制作为 NSCLC 的一种新型治疗策略，具有以下潜力： 提供可转化为临床的 OST 抑制剂。