Redox Modification and Targeting of Mutant KRas in Cancer

点击翻译按钮获取中文摘要

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.