Validation of OXPHOS gene amplification as a driver of hypoxia and treatment resistance in NSCLC

摘要 非小细胞肺癌(NSCLC)是一种高度侵袭性的疾病，通常在局部晚期或 转移期，预后差，治疗耐药率高，疾病发生率高 复发。非小细胞肺癌的临床治疗因分期不同而不同。大剂量立体定向全身放射治疗 治疗(SBRT)是局部非小细胞肺癌的标准治疗方案。然而，正如所发现的，不止 六十年前，肿瘤缺氧是有效放射治疗的重要障碍。在过去的十年里，第一条线 随着针对免疫的免疫疗法的引入，非小细胞肺癌的治疗得到了实质性的加强 检查点，如程序性细胞死亡1(PD-1)，但长期疾病控制发生在不到25%的 非小细胞肺癌患者。因此，了解治疗耐药的机制是必要的。 迫切需要引入新的协同疗法来提高缺氧性非小细胞肺癌的治疗反应 肿瘤。几十年来，肿瘤缺氧一直与抗癌治疗耐药有关，但它在 非小细胞肺癌的临床治疗在很大程度上仍未被探索。传统上，肿瘤缺氧的基础是 由于畸形的肿瘤血管不能满足肿瘤的高需求而导致氧气供应不足。 迅速增殖的肿块。然而，我们对癌症中非小细胞肺癌患者数据集的初步分析 基因组图谱(TCGA)泛癌数据集显示，高水平表达的 编码氧化磷酸化所必需的线粒体亚单位(OXPHOS)的核基因，以及高 低氧调节基因表达水平(Buffa低氧评分)。此外，我们还观察到一个直接的 几种主要氧磷酸盐基因拷贝数扩增(CNA)频率之间的正相关 基因和非小细胞肺癌患者样本中的低氧水平。因为线粒体功能消耗了高达90%的 可利用的细胞氧，其活性可能间接调节肿瘤中的氧供应。 当氧气被输送到肿瘤时，它会迅速消耗微环境。从机制上讲，这会导致 假设OXPHOS基因扩增驱动线粒体功能，而线粒体功能反过来可能促进肿瘤 低氧与非小细胞肺癌的治疗耐药因此，拟议的R03验证研究旨在确定 OXPHOS基因CNA高频表达在非小细胞肺癌肿瘤缺氧及耐药中的作用 肿瘤。完成后，这项研究将有助于目前对难治性疾病机制的理解。 在非小细胞肺癌患者中，并可能提供治疗结果的新标记物。

ABSTRACT Non-small cell lung cancer (NSCLC) is a highly aggressive disease typically diagnosed at locally advanced or metastatic stage, with dismal prognosis associated with high rates of treatment resistance and disease recurrence. Clinical management of NSCLC varies according to the stage. High-dose stereotactic body radiation therapy (SBRT) is the standard of care for localized non-resectable NSCLC. However, as discovered more than six decades ago, tumor hypoxia is a significant barrier to effective radiation therapy. In the last decade, first line NSCLC treatment has been substantially reinforced with the introduction of immunotherapy targeting immune checkpoints such as programmed cell death 1 (PD-1), yet long-term disease control occurs in less than 25% of NSCLC patients. Therefore, understanding the mechanisms of the treatment resistance is essential to address the dire need of introducing novel synergistic therapies to elicit enhanced treatment response in hypoxic NSCLC tumors. Tumor hypoxia has been associated with anti-cancer treatment resistance for decades, yet its role in clinical management of NSCLC remains largely unexplored. The basis of tumor hypoxia has traditionally been attributed to the oxygen supply deficit as malformed tumor vasculature fails to meet the high demand of the rapidly proliferating tumor mass. However, our preliminary analysis of NSCLC patient datasets in the Cancer Genome Atlas (TCGA) PanCancer dataset revealed a significant correlation between high-level expression of nuclear genes encoding mitochondrial subunits essential for oxidative phosphorylation (OXPHOS), and high- level expression of hypoxia-regulated genes (Buffa hypoxia score). Furthermore, we have observed a direct positive correlation between high frequency of copy number amplification (CNA) of several essential OXPHOS genes, and hypoxia levels in NSCLC patient samples. Because mitochondrial function consumes up to 90% of available cellular oxygen, its activity may be indirectly regulating oxygen availability in the tumor microenvironment by rapidly consuming oxygen upon its delivery to the tumor. Mechanistically, this leads to the hypothesis that OXPHOS gene amplification drives mitochondrial function which may, in turn, promote tumor hypoxia and treatment resistance in NSCLC. The proposed R03 validation study therefore aims to identify the role of high frequency of OXPHOS gene CNA in driving tumor hypoxia and treatment resistance of NSCLC tumors. Upon completion, this study will contribute to current understanding of mechanisms of refractory disease in NSCLC patients and may provide novel markers of treatment outcome.