The Ras pathway is one of the most commonly deregulated pathways in human cancer, yet there are still no effective therapies for Ras-driven tumors. In this application we will be studying two genetically distinct Ras-driven malignancies: NF1-mutant nervous system tumors (MPNSTs) and KRAS-mutant pancreatic cancers. Specifically, we aim to elucidate an important mechanism by which these Ras-driven cancers are protected from MEK inhibitors and will use this insight as a basis for developing and testing rational combination therapies. Collectively, these studies will reveal novel insight into innate mechanisms that protect these tumor types from Ras pathway inhibitors and will also lead to the development of several new therapeutic strategies that can be translated into clinical trials.