Abstract A13: KRAS4A directly regulates hexokinase 1

The KRAS oncogene is alternatively spliced, yielding KRAS4A and KRAS4B, which differ only in their membrane-targeting sequences. Tumors that harbor mutant KRAS manifest enhanced glucose utilization. We report a direct, GTP-dependent interaction between KRAS4A and hexokinase 1 (HK1) that alters the activity of the kinase, establishing HK1 as an effector of KRAS4A. The interaction is unique to KRAS4A because the palmitoylation/depalmitoylation cycle of this RAS isoform permits colocalization with HK1 on the outer mitochondrial membrane. Our findings constitute the first demonstration of direct regulation of a metabolic enzyme by a RAS protein and the first biochemical distinction between the KRAS splice variants. KRAS4A expression in cancer may drive unique metabolic vulnerabilities that can be therapeutically exploited. Citation Format: James P. Mahaffety, Caroline R. Amendola, Wei-Ching Chen, Alec Kimmelman, Allan Balmain, Mark R. Philips. KRAS4A directly regulates hexokinase 1 [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 A13.