Event Details:
Kevan Shokat
Professor and Chair
Department of Cellular and Molecular Pharmacology
University of California, San Francisco
Abstract
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. 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. These compounds rely on the mutant cysteine for binding and therefore do not affect the wild type protein (WT). I will discuss a new genome wide Crispr-i screen in K-RasG12C mutant cells treated with ARS-1620 to identify collateral dependencies which can be targeted in the clinic. I will also discuss ways to leverage immune cell killing of K-RasG12C cells treated with ARS-1620.