Mechanism of lung cancer resistance to tyrosine kinase inhibitor and radiation treatments

肺癌对酪氨酸激酶抑制剂和放射治疗的耐药机制

• 批准号: 10303868
• 负责人: BingHua Jiang
• 金额: $ 56.96万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303868
• 关键词: Animals; Apoptotic; Binding; Cancer Etiology; Cancer Patient; Cells; Chemotherapy and/or radiation; Correlation Studies; Data; Development; EZH2 gene; Endothelial Cells; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Exhibits; Future; Human; KDR gene; Laboratories; Lung; Lung Neoplasms; MDM2 gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mediating; MicroRNAs; Modeling; Molecular Biology; Oncogenic; Oxidative Stress; Patient-Focused Outcomes; Phenotype; Phosphorylation; Play; Promoter Regions; Proteins; Radiation; Radiation therapy; Receptor Signaling; Resistance; Role; Signal Pathway; Signal Transduction; Subgroup; Testing; Tissues; Tumor Angiogenesis; Tumor-Derived; Tyrosine Kinase Inhibitor; Vascular Endothelial Growth Factors; angiogenesis; cancer cell; cancer therapy; cohort; common treatment; improved; inhibitor/antagonist; interdisciplinary approach; mortality; new therapeutic target; novel therapeutics; overexpression; paracrine; radiation response; resistance mechanism; response; small molecule; targeted treatment; therapy resistant; treatment response; tumor; tumor growth

Lung cancer is the leading cause of cancer mortality worldwide. Abnormal oncogenic activation of EGFR signaling is one of major driver molecules for triggering lung cancer, small molecule tyrosine kinase inhibitors (TKI) have provided benefit for lung cancer patients, and radiation treatments are commonly used to improve the patient outcome. Recent studies from our laboratories show that oxidative stress and altered miRNA expression are important in therapeutic responses to radiation and chemotherapy. Our preliminary results demonstrate that persistent p70S6K1 activation and oxidative stress play an important role in resistant lung cancer cells upon TKI and radiation treatments, but not in sensitive cells. We also showed higher expression levels of NOX4 and EZH2 in the resistant cells that are resistant to TKI and radiation treatments. We hypothesize that p70S6K1 is induced by NOX4 and EZH2 overexpression, and miR-152 suppression and MDM2 are key downstream effectors for regulating lung cancer development and therapeutic resistance to targeted therapy and radiation treatment. We plan to test this hypothesis through three aims. Aim 1 is to determine role and mechanism of p70S6K1 in therapeutic resistance to TKI-targeted therapy and radiation treatment, and to identify p70S6K1 upstream regulators and downstream effectors for transmitting signal(s) for the treatment resistance. Aim 2 is to determine whether p70S6K1 induces lung tumor growth and TKI-targeted therapeutic resistance through MDM2 and miR-152 suppression using a lung orthotopic tumor model; and to determine whether p70S6K1 and NOX4 are required for tumor development using human lung cancer Patient-Derived Tumor (PDX) model. Aim 3 is to investigate whether levels of p70S6K1, NOX4, MDM2, and/or miR-152 are correlated with TKI-targeted therapy responses in lung cancer cohort; and are correlated with human lung cancer stages and survival; and to determine whether p70S6K1 regulates tumor angiogenesis through VEGF using a humanized chimeric tumor model. This R01 proposal will help to understand divergent resistant mechanisms in response to EGFR-TKI and radiation therapy. The successful completion of proposal will provide better understanding of lung cancer resistant mechanism and potential novel therapeutic option for lung cancer treatment in the future.

肺癌是世界范围内癌症死亡的主要原因。异常致癌的 EGFR信号传导的激活是触发肺癌的主要驱动分子之一，小 分子酪氨酸激酶抑制剂（TKI）为肺癌患者提供了益处， 放射治疗通常用于改善患者的结果。最近的研究来自 我们的实验室表明，氧化应激和改变的miRNA表达在 对放疗和化疗的治疗反应。我们的初步结果表明， 持续的p70 S6 K1激活和氧化应激在肺耐药中起重要作用 在TKI和放射治疗后的癌细胞中，而不是在敏感细胞中。我们还展示 - 在对TKI具有抗性的抗性细胞中N 0X 4和EZH 2的更高表达水平， 放射治疗我们假设p70 S6 K1是由NOX 4和EZH 2诱导的， miR-152抑制和MDM 2是细胞增殖的关键下游效应子。 调节肺癌发展和对靶向治疗的治疗抗性， 放射治疗我们计划通过三个目标来验证这一假设。目标1：确定 p70 S6 K1在TKI靶向治疗和放射治疗抵抗中的作用和机制 治疗，并确定p70 S6 K1的上游调节因子和下游效应因子， 传输用于治疗电阻的信号。目的2是确定p70 S6 K1是否 通过MDM 2和miR-152诱导肺肿瘤生长和TKI靶向治疗耐药性 使用肺原位肿瘤模型测定p70 S6 K1和p70 S6 K2的表达; N 0X 4是使用人肺癌的肿瘤发展所必需的 (PDX)模型目的3是研究p70 S6 K1、NOX 4、MDM 2和/或miR-152的水平是否与细胞凋亡相关。 与肺癌队列中的TKI靶向治疗反应相关;并且 与人肺癌分期和存活率的关系;并确定p70 S6 K1是否调节 使用人源化嵌合肿瘤模型通过VEGF的肿瘤血管生成。R 01提案 将有助于了解不同的耐药机制，在响应EGFR-TKI和辐射 疗法成功完成提案将使人们更好地了解肺癌 耐药机制和潜在的新的治疗选择， 未来