Abstract IA03: KRAS Q61H preferentially signals through the MAPK pathway in non-small cell lung cancer

Abstract

Abstract RAS proteins are guanosine triphosphatases (GTPases) that function as binary switches cycling between inactive (GDP-bound) and active (GTP-bound) states. Activated RAS proteins bind RAS effectors including RAF kinases, PI3K, RalGDS, and others. Conversion from GDP to GTP is stimulated by guanine nucleotide exchange factors (GEFs) while conversion to the inactive GDP-bound form is mediated by GTPase activating proteins (GAPs). Mutations can alter the signaling properties of RAS proteins through a number of means including modification of the GTPase activity, nucleotide exchange rate, or effector binding characteristics. Understanding these differences may enable new therapeutic approaches to specific RAS mutations associated with human disease. We will discuss how codon 61 mutations in KRAS can result in profoundly reduced intrinsic and GAP-stimulated GTPase activity, and a relatively high affinity for RAF-RBD compared to other oncogenic KRAS mutations, and how these features may enable therapeutic options for cancers bearing RAS mutations at codon 61. Citation Format: Zhiwei Zhou, Chiara Ambrogio, Asim Bera, Li Qing, Xu Cheng-Xiong, Pasi Janne, Ken Westover. KRAS Q61H preferentially signals through the MAPK pathway in non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA03.