Role of KSR in tumorigenesis and the radiation response

KSR 在肿瘤发生和放射反应中的作用

• 批准号: 6556262
• 负责人: Hongmei Rosie XING
• 金额: $ 22.63万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6556262
• 关键词: Caenorhabditis elegans; Drosophilidae; MCF7 cell; arthropod genetics; athymic mouse; biological signal transduction; bladder neoplasm; carcinogenesis; disease /disorder model; epidermal growth factor; gene targeting; genetically modified animals; growth factor receptors; guanine nucleotide binding protein; ionizing radiation; mitogen activated protein kinase; neoplasm /cancer radiation therapy; neoplastic growth; nonhuman therapy evaluation; oligonucleotides; oncogenes; phosphatidylinositol 3 kinase; protein structure function; radiation related neoplasm /cancer; radiation resistance; radiation sensitivity; radiosensitizer

DESCRIPTION (provided by applicant): The long-term goal of this project is to explore the molecular mechanisms underlying cellular sensitivity to ionizing radiation (IR) and to devise strategies to regulate radiosensitivity by manipulating signal transduction events. Signal transduction events, especially those mediated by the oncogenic Ras and epidermal growth factor receptor (EGFR), can significantly alter the radiosensitivity of tumor cells and cause them to become more resistant to ionizing radiation-induced cell killing. However, the precise mechanisms underlying the actions of EGFR and Ras are not well understood. This application proposes to adopt a multidisciplinary (biochemical, genetic and pharmacologic) approach to define the role of Kinase Suppressor of Ras (KSR), a newly identified component of the EGFRIRaslRaflMAPK signaling pathway, in EGFR/Ras-mediated tumorigenesis and radio-response to IR. The hypotheses to be explored in this project are 1) oncogenic gf Ras, and hyper-activated wild-type (wt) Ras as a result of constitutively activated EGFR, signal oncogenesis via KSR; and 2) KSR is required for Ras-mediated radioresistance to IR. Specific aims to address these hypotheses are: 1) to investigate the role of KSR in EGFR/Ras tumorigenesis using transplanted human tumors, 2) to evaluate the role of KSR in EGFR/Ras-mediated responses to IR, and 3) to explore the potential of KSR as a molecular target for radiation therapy in various human tumors, specifically, the feasibility of using antisense oligodeoxynucleotide (AS-ODN) as a radiosensitizer. Results from these studies may offer new insights into the biological functions of KSR, which at this moment are largely unknown. Concomitantly, these investigations will help to identify new elements of Ras signaling which may have implications not only for the utility of KSR AS-ODNs in tumors with oncogenic ras mutations, but also in tumors with a highly activated wt Ras pathway as a result of overexpression of growth factors and/or their receptors. In summary, elucidation of KSR as an essential component of the EGFR/Ras-mediated tumorigenesis and cellular response to IR will potentially offer a highly tumor-specific molecular target for the development of diagnostic and therapeutic tools to treat a variety of human malignancies dependent on EGFR/Ras signaling.

描述（由申请人提供）：该项目的长期目标是探索细胞对电离辐射（IR）敏感性的分子机制，并制定通过操纵信号转导事件来调节放射敏感性的策略。信号转导事件，尤其是由致癌 Ras 和表皮生长因子受体 (EGFR) 介导的信号转导事件，可以显着改变肿瘤细胞的放射敏感性，并使它们对电离辐射诱导的细胞杀伤变得更加耐受。然而，EGFR 和 Ras 作用的确切机制尚不清楚。本申请拟采用多学科（生化、遗传学和药理学）方法来定义 Ras 激酶抑制剂 (KSR)（一种新鉴定的 EGFRIRaslRaflMAPK 信号通路成分）在 EGFR/Ras 介导的肿瘤发生和放射反应中的作用。红外。本项目要探讨的假设是 1) 致癌 gf Ras 和由于 EGFR 持续激活而过度激活的野生型 (wt) Ras，通过 KSR 发出肿瘤发生信号； 2) Ras介导的IR放射抗性需要KSR。解决这些假设的具体目标是：1）利用移植的人类肿瘤研究 KSR 在 EGFR/Ras 肿瘤发生中的作用，2）评估 KSR 在 EGFR/Ras 介导的 IR 反应中的作用，以及 3）探索KSR 作为各种人类肿瘤放射治疗分子靶点的潜力，特别是使用反义寡脱氧核苷酸（AS-ODN）作为放射增敏剂的可行性。这些研究的结果可能为目前很大程度上未知的 KSR 生物学功能提供新的见解。与此同时，这些研究将有助于识别 Ras 信号传导的新元件，这可能不仅对 KSR AS-ODN 在具有致癌 ras 突变的肿瘤中的应用产生影响，而且对因过度表达而导致 wt Ras 通路高度激活的肿瘤产生影响生长因子和/或其受体的。总之，阐明 KSR 作为 EGFR/Ras 介导的肿瘤发生和细胞对 IR 反应的重要组成部分，将有可能为开发诊断和治疗工具提供高度肿瘤特异性的分子靶点，以治疗依赖于EGFR/Ras 信号传导。