Many genetic alterations are known to occur in lung cells that become cancerous.  One of the most prevalent of these is a mutation in a gene called Kras.  Despite years of investigation, it is still not clear why mutation in this gene is so frequent in lung cancer and how it alters normal cells to turn them into cancer cells. In addition, we have not been successful in developing therapeutic agents that specifically target cells that carry Kras mutations. In our laboratory we use a mouse model in which a mutated form of Kras very similar to the one found in human lung cancer can be turned on using an enzyme called Cre recombinase. By using this model system, we have already learned much about how Kras functions as an oncogene in the context of a living organism.

Previous work from many investigators has shown that Kras mutation results in changes in the way proteins inside cells communicate with each other.  These are called “signaling cascades.”  Which signaling cascades are important in what tissues has not been well defined. We are trying to identify what signaling cascades are altered in lung tumor cells in which Kras is mutated. To do this, we use a technique called RNA interference.  Using this technique, we are able to “turn off” the expression of genes involved in specific signaling cascades. We have used a technique called gene expression microarrays to identify genes that are altered when Kras is mutated. Using RNA interference, we have carried out a screen to identify which genes from the microarray experiments are most important for tumor cells that carry Kras mutation. Our preliminary results have identified several genes that may have novel functions in Kras signaling cascades.  Here we propose experiments to further analyze how these genes function and whether they might represent novel targets for therapy.

The work we propose is of direct relevance to the search for novel therapeutic approaches to treat human cancer.  Understanding how cells in a living organism respond to Kras activation will allow us to find novel treatments.  These could be given at the same time as chemotherapy to make it more effective. We can test these novel therapies in the mouse model to see if they work.  This will provide us with important information in defining what targets are most likely to work in human patients.