Ras Signaling in Cancer

Kras is one of the most frequently mutated genes in human cancer. Many signaling pathways (MAPK, AKT, RALGDS) have been described as being necessary for Kras induced oncogenic transformation. However, the specific pathways requiredare strongly dependent on the tissue origin (fibroblast vs. epithelial cell etc). Our laboratory is interested in identifying key regulators of oncogenic Krasfunction with the ultimate goal of identifying novel “synthetic lethal” interactions that couldbe used for therapy.

Using cross-species microarray analysis to compare a mouse model of lung cancer to human disease, we previously uncovered a gene expression profile associated with Kras mutation across species and in different tissues (Sweet-Cordero, et al Nature Genetics 2005). To test the functional significance of this signature, we developed a novel method for doing negative selection with pooled lentiviral shRNAs. Using this approach, we identified Wilm’s tumor-1 (WT1) as key regulator of Ras-induced senescence. Loss of WT1 leads to senescence in both mouse and human cells that express oncogenic Kras. In addition, we have found that loss of Wt1 significantly decreases lung tumor burden in the KrasG12D/+ mouse model (Vicent et al, Journal of Clinical Investigation, 2010). A key goal of our laboratory is to understand how Wt1 interacts with Ras to regulate senescence. Current studies are directed at identifying Wt1 interacting proteins.

We also recently demonstrated that KRAS regulates a NRF2-ATF4-ASNS axis that is critical for the response to nutrient stress (Gwinn et al Cancer Cell 2018). We are interested in understanding how this nutrient stress response can be exploited for therapeutic benefit in lung cancer and other cancers. In otherhighly impactful work, we recently have demonstrated that the CLCF1-CNTFR axis is a relevant therapeutic target that may be particularly important for KRAS mutant lung cancer (Marquez et al, Nature Medicine 2019).

More generally, we are exploiting new tools for genetic analysis (CRISRP, CRISPRi) to identify new vulnerabilities in the Ras pathway. We are part of the NCI-funded Ras consortium and a well-established collaboration with the laboratories of Michael Bassik and Peter Jackson (both at Stanford) to further these studies. A key goal of our effortsin this regard is to use genetically engineered tumor models to determine how Ras vulnerabilities are influenced by genetic context.