Aron Hobbs, Ph.D.: Department of Cell & Molecular Pharmacology & Experimental Therapeutics
To date, no effective pan-KRAS mutation therapies exist (3). The KRASG12D mutation represents the most common KRAS mutation in PDAC followed by KRASG12V and KRASG12R. However, the KRASQ61L mutation, for example, is non-existent in PDAC despite being highly oncogenic in model systems. These data suggest that KRAS mutations are not equivalent and each mutant may regulate distinct as well as overlapping signaling pathways. My work on KRASG12R supports this hypothesis. Unlike many KRAS mutants, KRASG12R cannot bind to PI3K, a well-studied KRAS effector necessary for RAS mediated tumorigenesis (4). Nevertheless, KRASG12R is an important driver of PDAC. Building on these observations, we will determine the distinct as well as overlapping protein interactions and effector signaling of specific KRAS mutants. Towards this end, we will define the mutation-specific signaling vulnerabilities of KRAS mutants utilizing both 2D and 3D cell models. We will employ Biotin Identification (BioID) proximity ligation assays to define the mutation specific protein interactions. Thus, we will begin to unravel the mystery as to why select KRAS mutants, such as KRASG12R but not KRASQ61L, promote PDAC. We hypothesize that the mutant-specific effector interactions in KRAS-initiated PDAC will illuminate which pathways are most susceptible to therapeutic disruption in PDAC.
Finally, we propose to expand the Cell Models core of the COBRE Digestive and Liver Disease (CDLD) to include the generation of mouse- and patient-derived pancreatic organoids for use in our studies and others at MUSC.
