Kras is a gene frequently mutated in human lung cancer. Despite years of investigation, no targeted therapeutics for Kras signaling pathways has proven to be effective in human patients.   One reason for this may be an incomplete understanding of how Kras functions as an oncogene in vivo.  For example, we know little about how Kras effector pathways may differ from those of other Ras family members and how this specificity may be tissue-dependent.  In addition, it is not clear why Kras mutations are found in some tumor types and not in others. The overall goal of this project is to identify effectors that mediate the oncogenic effects of Kras in lung epithelium in vivo  that may be amenable to therapeutic intervention.  Our hypothesis is that some genes that are downstream of Kras may act may be critical to maintenance of the oncogenic state and therefore that there downregulation may have a  “synthetic lethal” effect on Kras mutant  tumor cells.
Our previous work has characterized a gene expression signature of Kras mutation in mouse and human lung tumors.  We have now carried out an shRNA-based genetic screen to test the functional significance of this signature and its upstream transcriptional regulators.  This screen has identified several “hits” that we have now begun to validate. Here we propose further functional analysis in vitro and in vivo to determine the role of genes we have identified through this screen in Kras induced oncogenesis. We have developed a novel lentiviral vector for shRNA delivery to the lung epithelium.  This will allow us to test the functional significance of genes from our screen in both tumor initiation and tumor maintenance in a Kras-context.   Targets that are confirmed as specific for Kras-induced oncogenesis will be selected for further gene-expression based identification of potential chemical inhibitors.