OST Inhibition in NSCLC

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，系统疗法的引入，如受体酪氨酸 激酶靶向抑制剂和免疫检查点抑制剂显著改善了患者的预后。 然而，对这些疗法的治疗耐药性经常出现，其特点是平行 通过其他共表达的受体糖蛋白传递信号。因此，我们研究了 作为一种策略，干扰天冬酰胺(N)连接的糖基化，这是一种共翻译和翻译后蛋白质修饰 阻断非小细胞肺癌原发糖蛋白生存信号和旁路糖蛋白生存信号。虽然这条路径是目标 富含并涉及至少34种基因产物，调节这一过程的药物抑制剂尚未 以前是可用的。我们已经确定了一种一流的小分子抑制剂 寡糖转移酶(OST)，多亚单位酶复合体，将多糖转移到伸长 内质网中的蛋白质。这种抑制物通过靶向催化亚单位和 结果导致位点特异性和部分抑制糖基化。非小细胞肺癌中依赖RTK的激活 致癌信号，OST抑制阻止肿瘤细胞增殖，并有利地与TKI结合以增强 细胞凋亡与异种移植瘤生长我们现在建议对新型小分子进行表征和改进 与催化亚单位抑制有关的OST抑制剂以及对EGFR驱动的非小细胞肺癌的影响。因为 糖蛋白旁路信号在有FGFR1扩增或KRAS的NSCLC亚型中也起作用 突变，我们将定义信号机制，并确定这些肿瘤对OST的敏感性 抑制力。该项目还将调查OST抑制对非小细胞肺癌放射敏感性的影响，并确定 糖蛋白依赖的细胞程序如何介导固有和免疫介导的治疗耐药。 总之，这项工作将推动OST抑制作为一种新的非小细胞肺癌治疗策略，具有潜在的 提供一种可以转化为临床的OST抑制剂。

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.