Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects

摘要

Abstract The crystal structure of RAS was first solved 25 years ago. In spite of tremendous and sustained efforts, there are still no drugs in the clinic that directly target this major driver of human cancers. Recent success in the discovery of compounds that bind RAS and inhibit signaling has fueled renewed enthusiasm, and in-depth understanding of the structure and function of RAS has opened new avenues for direct targeting. To succeed, we must focus on the molecular details of the RAS structure and understand at a high-resolution level how the oncogenic mutants impair function. Structural networks of intramolecular communication between the RAS active site and membrane-interacting regions on the G-domain are disrupted in oncogenic mutants. Although conserved across the isoforms, these networks are near hot spots of protein-ligand interactions with amino acid composition that varies among RAS proteins. These differences could have an effect on stabilization of conforma-tional states of interest in attenuating signaling through RAS. The development of strategies to target these novel sites will add a fresh direction in the quest to conquer RAS-driven cancers. Introduction RAS GTPase is a master signaling protein at the hub of numerous signal transduction pathways, responding to upstream signals from a variety of sources and interacting with a wide range of effector proteins to regulate cell proliferation, survival, migration, and apoptosis (1). Signal transduction pathways involving RAS are illustrated in McCormick's overview of this CCR Focus series (2). The three major isoforms of RAS, KRAS, NRAS, and HRAS together are mutated in about 20% of human cancers, primarily in the active site at residues G12, G13, and Q61 near the y-phosphate of the guanosine triphosphate (GTP) substrate (Fig. 1). RAS GTPases are, therefore, among the most urgent targets for the treatment of cancer. Yet, to date, there are no drugs in the clinic that directly target RAS, and thus, these proteins have come to be thought of as undruggable. The current state of directly drugging the G-domain of RAS is the subject of this review. Targeting post-translational modifications at the C-terminus is discussed by Cox and colleagues (3) in this CCR Focus series, while alternative strategies focused on altered metabolic pathways driven by RAS mutants and synthetic lethality approaches are reviewed by Kimmelman (4) and Downward (5), respectively.