LAUSR

Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer and are generally associated with poor response to standard therapies. Efforts to directly target this oncogene have faced difficulties due to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites (1). Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent upon relative nucleotide affinity and concentration. This gives GTP an advantage over GDP and increases the proportion of active GTP-bound Ras. I will discuss the development of small molecules that irreversibly bind to a common oncogenic mutant, K-RasG12C (2). These compounds rely on the mutant cysteine for binding and therefore do not affect the wild-type protein (WT). Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. These data provide structure-based validation of a novel allosteric regulatory site on Ras that is targetable in a mutant-specific manner. References 1. Stephen AG, Esposito D, Bagni RK, McCormick F. Dragging Ras back in the ring. Cancer Cell 2014;25: 272–81. 2. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. Nature 2013;12796:503, 548–51. Citation Format: Kevin Shokat. Targeting K-Ras directly [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 IA18.