Raf-1 As a Regulator of Glutamine Metabolism

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PROJECT SUMMARY The Ras proteins are frequently mutated in cancer to activate diverse signaling pathways necessary for uncontrolled cellular proliferation, including pathways responsible for regulating metabolism. Ras is capable of coordinating these many pathways through its many effectors. Though the large number of tumors driven by HRAS, NRAS, and KRAS mutations makes the protein an attractive drug target, its structure and complex regulation have limited the development of effective small molecule inhibitors. Because Ras itself is difficult to target, understanding which of its effectors are critical for its function in an oncogenic context is necessary. To this end, the Khavari lab had previously conducted a CRISPR screen of Ras-interactors to identify effectors that were necessary for Ras-driven tumor maintenance. Across tissue types, we observed a dependence on Raf-1 in oncogenic Ras-driven cancer cells. Follow- up experiments on Raf-1 revealed that oncogenic Ras induced mitochondrial translocation of Raf-1 and novel regulators of glutamine metabolism interacting with the protein. Subsequent experiments demonstrated that loss of Raf-1 led to decreased glutamine metabolism in a mutant Ras-dependent manner. This work suggests that Raf-1 is a specific vulnerability of Ras-driven tumors due to its role in directly coordinating metabolic processes. It is well-known that cancer cells rewire their metabolism and this leads to certain metabolic vulnerabilities, but targeting those vulnerabilities remains a challenge. This work aims to understand the role of Raf-1 in regulating glutamine metabolism in Ras-driven cancer cells. We hypothesize that the Raf-1 protein directly regulates glutamine metabolism in Ras-driven tumors. In Aim I, I will elucidate the impact of Raf-1 on glutamine metabolism by defining the relationship between Raf-1 and glutamine metabolic enzymes. In Aim II, I will determine the mechanism of Ras- induced mitochondrial matrix localization. Overall, this work will provide a novel mechanism for Ras- induced alterations to cancer metabolism.