Redox Modification and Targeting of Mutant KRas in Cancer

癌症中突变 KRa 的氧化还原修饰和靶向

• 批准号: 9912729
• 负责人: Kate Suzanne Carroll
• 金额: $ 43.46万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912729
• 关键词: 3-Dimensional; Acinar Cell; Address; Alanine; Alleles; Biological Assay; Biological Markers; Cell Line; Cell Proliferation; Cell physiology; Cells; Chemicals; Collaborations; Critical Pathways; Cysteine; Data; Detection; Development; Diagnosis; Disease; Drug Targeting; Early Diagnosis; Early treatment; Ensure; Environment; Event; Future; Goals; Growth; Growth Factor; Human; In Situ; KRAS2 gene; Knowledge; Laboratories; Learning; Lesion; Libraries; Link; Malignant Neoplasms; Malignant neoplasm of pancreas; Maps; Metabolic; Methods; Modification; Molecular; Mus; Mutation; NF-kappa B; Neoplasms; Oncogenes; Oncogenic; Oxidation-Reduction; Oxides; Pancreas; Pancreatic carcinoma; Pathway interactions; Pharmacology; Phosphorylation; Point Mutation; Post-Translational Protein Processing; Process; Production; Property; Protein Kinase; Reactive Oxygen Species; Reporter Genes; Reporting; Research; Role; Sentinel; Signal Pathway; Signal Transduction; Signaling Protein; Site; Stress; Sulfenic Acids; Sulfhydryl Compounds; Testing; Time; base; cancer cell; cancer initiation; cancer therapy; chemoproteomics; cysteinesulfenic acid; design; expectation; experimental study; inhibitor/antagonist; innovative technologies; insight; migration; mutant; novel; oxidation; pancreas development; premalignant; protein biomarkers; small molecule; therapeutic target; tumorigenesis; tumorigenic

ABSTRACT Oncogenic mutation of KRAS is a signature event in progression and growth of pancreatic cancer, an almost universally fatal disease. Oncogenic KRAS allele expression leads to metabolic changes and altered cellular signaling pathways that both stimulate the production of intracellular reactive oxygen species (ROS). Increases in ROS drive formation and progression of pancreatic precancerous lesions by upregulating survival and growth factor signaling pathways. Despite ROS dysregulation being central to cancer cell proliferation, as exemplified by KRas-induced tumorigenesis, the mechanisms underlying ROS-dependent neoplasia remain very poorly understood. Elucidation and characterization of the redox-dependent ‘switches’ that support ROS-driven neoplasia have been severely hampered by the lack of direct methods to examine oxidative cysteine modifications in their native cellular environment. Our laboratory has addressed this challenge through the development of a chemoproteomic approach for in situ detection of the prototypical protein biomarker of redox signaling and stress, known as cysteine sulfenic acid (Cys-SOH or S-sulfenylation). Here, we apply state-of-the-art methods to accomplish our major objectives of: 1) site- specific mapping and characterization of KRasmut-dependent cysteine-based redox ‘switches’ that support development of pancreatic cancer, and 2) examining the tumorigenic potential and pharmacological impact of oxidative modification at the acquired cysteine in mutant KRasG12C. Successful completion of this project will identify oxidative cysteine modification as an integral feature of processes that initiate pancreatic cancer through mutant KRas. It will also delineate the relationship between oxidative modification of the redox-active thiol of KRasG12C to its tumorigenic potency and the efficacy of small-molecules designed to target this mutant. It will also define the role of redox in tumorigenic potency of KRasG12C and the efficacy of small-molecules designed to target this mutant. In addition to KRas itself, the molecular components of redox pathways identifying during this study may represent new biomarkers and drug targets for the early diagnosis and treatment of pancreatic cancer.

抽象的 KRAS 的致癌突变是胰腺癌进展和生长的标志性事件，几乎是一种 普遍致命的疾病。致癌 KRAS 等位基因表达导致代谢变化和细胞信号传导改变 刺激细胞内活性氧（ROS）产生的途径。 ROS 驱动力增加 通过上调生存和生长因子信号传导来促进胰腺癌前病变的形成和进展 途径。尽管 ROS 失调是癌细胞增殖的核心，如 KRas 诱导的那样 尽管对于肿瘤发生来说，ROS 依赖性肿瘤形成的机制仍然知之甚少。说明 支持 ROS 驱动肿瘤形成的氧化还原依赖性“开关”的表征已受到严重影响 由于缺乏直接方法来检查其天然细胞中的氧化半胱氨酸修饰而受到阻碍 环境。我们的实验室通过开发化学蛋白质组学方法解决了这一挑战 用于原位检测氧化还原信号和应激的原型蛋白质生物标志物，称为半胱氨酸磺酸 （Cys-SOH 或 S-磺酰化）。在这里，我们应用最先进的方法来实现我们的主要目标：1) 站点- KRasmut 依赖的基于半胱氨​​酸的氧化还原“开关”的特定映射和表征，支持 胰腺癌的发展，以及 2) 检查其致瘤潜力和药理学影响 突变体 KRasG12C 中获得性半胱氨酸的氧化修饰。该项目的成功完成将确定 氧化半胱氨酸修饰是通过突变 KRas 引发胰腺癌的过程的一个组成部分。 它还将描述 KRasG12C 的氧化还原活性硫醇的氧化修饰与其 致瘤效力和针对该突变体设计的小分子的功效。它还将定义以下角色： 氧化还原对 KRasG12C 致瘤能力的影响以及针对该突变体设计的小分子的功效。在 除了 KRas 本身之外，本研究期间确定的氧化还原途径的分子成分可能代表 用于胰腺癌早期诊断和治疗的新生物标志物和药物靶点。