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（IR），并制定策略来通过操纵信号转导事件来调节放射性敏感性。信号转导事件，尤其是由致癌性RA和表皮生长因子受体（EGFR）介导的事件，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具有更大的抵抗力。但是，EGFR和RAS行为的基础机制尚不清楚。该申请建议采用多学科（生化，遗传和药物）方法来定义RAS（KSR）激酶抑制器（KSR）的作用，RAS（KSR）是EGFRIRASLRAFLMAPK信号途径的新鉴定的成分，在EGFR/RAS介导的肿瘤和无线电肿瘤和无线电上偏置中。该项目中要探索的假设是1）致癌GF RAS，以及由于组成症激活的EGFR，通过KSR通过KSR的信号肿瘤而导致的过度激活的野生型（WT）RAS； 2）KSR是RAS介导的对IR的辐射率所必需的。解决这些假设的具体目的是：1）研究KSR在使用移植的人类肿瘤中研究KSR在EGFR/RAS肿瘤中的作用，2）评估KSR在EGFR/RAS介导的IR的反应中的作用，而3）在探索KSR作为分子治疗的潜在的各种人类的分子治疗中，特异性地，特异性地探索了各种人类的分子治疗，从而探索了各种人类的含量。寡脱氧核苷酸（AS-ODN）作为放射性敏感剂。这些研究的结果可能会为KSR的生物学功能提供新的见解，而KSR目前在很大程度上尚不清楚。同时，这些研究将有助于确定RAS信号的新元素，这可能不仅对具有致癌性RAS突变的肿瘤中的KSR AS-ODN有影响，而且在具有高度激活的WT RAS途径的肿瘤中，由于生长因子和/或其受体的过表达而导致的WT RAS途径。总而言之，将KSR阐明是EGFR/RAS介导的肿瘤发生的重要组成部分，并且对IR的细胞反应可能会提供一个高度肿瘤特异性的分子靶标，用于开发诊断和治疗工具，以治疗依赖于EGFR/RAS信号的各种人类恶性肿瘤。