Abstract IA14: Targeting Ras

Abstract

Abstract We are exploring multiple ways of targeting Ras proteins and Ras-driven cancers. We have identified compounds that covalently bind to cysteine-185 on K-Ras 4B, and to the G-domain of K-Ras 4A and 4B. We are also screening for compounds that bind directly to K-Ras using a new technique referred to as Second Harmonic Generation and are developing compounds that promote phosphorylation of K-Ras4B on serine-181. In addition, we are attempting to solve novel structures of oncogenic Ras proteins on their own, or complexed with effectors, regulators and chaperones, in an attempt to identify new targeting opportunities. For example, we have solved the structure of fully processed K-Ras 4B bound to PDE-delta. This co-structure suggests several new approaches to targeting K-Ras processing. In addition to targeting K-Ras directly, we are validating downstream dependencies that are specific for K-Ras cancers, including the cytokine LIF, which is expressed at high levels in K-Ras transformed cells and plays a major role in stem-like properties of K-Ras cancers. Suppressing LIF expression using shRNA, CRISPR or monoclonal antibodies has profound effects on K-Ras tumor initiation and maintenance, and suggests new therapeutic opportunities. We are also analyzing signaling pathways that differ between Ras mutants and between Ras isoforms. These results, and their opportunities for intervention, will be discussed. Citation Format: Frank McCormick. Targeting Ras. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA14.