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 活化的EGFR信号是触发肺癌的主要驱动分子之一 分子酪氨酸激酶抑制剂(TKI)为肺癌患者提供了益处， 放射治疗通常被用来改善患者的预后。最近来自 我们的实验室表明，氧化应激和改变的miRNA表达在 对放射和化疗的治疗反应。我们的初步结果表明， 持续的p70S6K1激活和氧化应激在耐药肺中起重要作用 TKI和放射治疗中的癌细胞，但不在敏感细胞中。我们还展示了 在对TKI和EZH2耐药的细胞中NOX4和EZH2的高表达水平 放射治疗。我们假设p70S6K1是由NOX4和EZH2诱导的 高表达，miR-152抑制和MDM2是关键的下游效应因子 调控肺癌的发展和对靶向治疗的耐药性 放射治疗。我们计划通过三个目标来检验这一假设。目标1是确定 P70S6K1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p70S6K1上游调节因子和下游效应子 传递抗病信号(S)。目的2是确定p70S6K1是否 MDM2和miR-152诱导肺癌生长及TKI靶向治疗耐药 利用肺原位肿瘤模型进行抑制；并确定p70S6K1和p70S6K1是否 NOX4是利用人肺癌患者来源的肿瘤发生所必需的 (PDX)模型。目的3是研究p70S6K1、NOX4、MDM2和/或miR-152的水平 在肺癌队列中与TKI靶向治疗反应相关；并且相关 与人类肺癌分期和生存期的关系；并确定p70S6K1是否调节 利用人源化嵌合肿瘤模型通过血管内皮生长因子促进肿瘤血管生成。本R01建议书 将有助于了解EGFR-TKI和辐射的不同耐药机制 心理治疗。提案的成功完成将使人们对肺癌有更好的了解 肺癌耐药机制及潜在的肺癌治疗新选择 未来。