Interruption of cholesterol metabolism and replication stress response in cancer therapy

癌症治疗中胆固醇代谢和复制应激反应的中断

• 批准号: 10044013
• 负责人: Junran Zhang
• 金额: $ 40.11万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044013
• 关键词: ATR checkpoint; Adenocarcinoma Cell; Affect; Antifungal Agents; Atlases; Biochemical; Biological; Biological Assay; CHEK1 gene; Cancer Etiology; Cancer Patient; Cell Cycle Checkpoint; Cell Death; Cell Line; Cell Proliferation; Cell Survival; Cells; Cessation of life; Cholesterol; Cholesterol Homeostasis; Clinical Trials; Correlation Studies; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA replication fork; Data; Development; Disease; Drug Targeting; Enzyme Inhibition; Enzymes; FDA approved; Fiber; Genes; Goals; Human; Immunotherapy; Incidence; Interruption; Lead; Liquid Chromatography; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Metabolic; Metabolism; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Oncology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phosphotransferases; Process; Protein Inhibition; Proteins; Reactive Oxygen Species; Reporting; Signal Transduction; Single-Stranded DNA; Squalene; Squamous cell carcinoma; Stress; Testing; The Cancer Genome Atlas; Therapeutic Intervention; Time; Xenograft procedure; antitumor effect; ataxia telangiectasia mutated protein; base; biological adaptation to stress; cancer cell; cancer therapy; cholesterol biosynthesis; epoxidase; genome-wide; improved; in vitro Assay; in vivo; inhibitor/antagonist; knock-down; liquid dynamics; loss of function; mortality; mouse model; novel; novel strategies; novel therapeutic intervention; outcome forecast; overexpression; replication stress; response; small hairpin RNA; tandem mass spectrometry; targeted cancer therapy; targeted treatment; therapy resistant; transcription factor; treatment strategy; tumor; tumor growth

Project Summary: Lung cancer is the most common malignancy worldwide, both in incidence and mortality. Unfortunately, this disease is often driven by activating oncogenes that are either not amenable to direct therapeutic intervention or when targeted therapies are available treatment resistance invariably develops, thus highlighting the urgent need for the development of novel treatment strategies. Metabolic reprogramming is a hallmark of cancer and is a pharmaceutical target for cancer therapy. SQLE, a key enzyme required for cholesterol synthesis, is frequently overexpressed in lung cancer and is associated with poor prognosis. Excitingly, our recent genome-wide loss of function screen discovered that SQLE reduction caused enhanced sensitivity to an inhibitor targeting CHK1, a key DNA damage response (DDR)/replication stress (RS) response protein that is required for cell survival and proliferation under RS. Our preliminary data suggest that SQLE inhibition by shRNA knockdown causes RS and activates ATR/CHK1 signaling. Thus, the goal of this application is to determine whether high SQLE-expressing lung cancer can be specifically targeted by the combined inhibition of SQLE and CHK1 or its upstream factor ATR. Because the inhibition of proteins required for cholesterol biosynthesis leads to decreased dNTP and increased reactive oxygen species (ROS) (i.e., two common mechanisms for RS ), we hypothesize that SQLE inhibition leads to increased RS by deregulation of dNTP and/or ROS, triggering the ATR/CHK1 axis for survival. Thus, co-administration of an SQLE inhibitor and an ATR or CHK1 inhibitor could synergistically suppress tumor growth of lung cancer. Specific Aim 1 will delineate whether SQLE inhibition-induced RS is associated with perturbation of the dNTP pool and increased ROS, using liquid chromatography-tandem mass spectrometry, DNA fiber assays and biochemical/cell biological approaches. Specific Aim 2 will assess the antitumor effects of the combined inhibition of SQLE and RS response proteins using in vitro assays and cell line-based and patient-derived xenograft (PDX) mouse models of lung cancer. If successful, our studies will have a significant impact on improving the survival of lung cancer patients by identifying novel therapeutic approaches.

项目概述：肺癌是世界范围内最常见的恶性肿瘤，无论是发病率还是死亡率。 不幸的是，这种疾病通常是由激活癌基因驱动的，这些癌基因要么不适合直接 治疗性干预或当靶向治疗可用时，治疗抗性总是发展，因此， 强调迫切需要开发新的治疗策略。代谢重编程是一种 是癌症的标志，并且是癌症治疗的药物靶标。SQLE，一种关键酶， 胆固醇合成，经常在肺癌中过度表达，并与预后不良有关。 令人兴奋的是，我们最近的全基因组功能缺失筛选发现，SQLE减少导致增强的 对靶向CHK 1的抑制剂的敏感性，关键的DNA损伤反应（DDR）/复制应激（RS）反应 在RS下细胞存活和增殖所需的蛋白质。我们的初步数据表明，SQLE 通过shRNA敲低的抑制导致RS并激活ATR/CHK 1信号传导。因此， 应用是确定高SQLE表达的肺癌是否可以被特异性地靶向。 SQLE和CHK 1或其上游因子ATR的联合抑制。因为蛋白质的抑制需要 导致dNTP降低和活性氧（ROS）增加（即，两 RS的共同机制），我们假设SQLE抑制通过以下方式导致RS增加： dNTP和/或ROS，触发ATR/CHK 1轴生存。因此，共同施用SQLE抑制剂和 ATR或CHK 1抑制剂可以协同抑制肺癌的肿瘤生长。具体目标1将 描述SQLE抑制诱导的RS是否与dNTP池的扰动相关， ROS，使用液相色谱-串联质谱法，DNA纤维测定和生化/细胞 生物学方法。具体目标2将评估SQLE和 使用体外测定和基于细胞系和患者来源的异种移植（PDX）小鼠的RS应答蛋白 肺癌的模型如果成功，我们的研究将对提高肺移植患者的生存率产生重大影响。 癌症患者通过识别新的治疗方法。