Neurofibromatosis type 1 (NF1) is a genetic disease affecting approximately 1 in 3,000 individuals. Patients have a 10% lifetime risk of developing malignant peripheral nerve sheath tumors (MPNST). These highly aggressive cancers are the leading cause of death for NF1 patients. There are currently no effective therapies for treating MPNST, underscoring the urgent medical need to identify new treatment options. One class of drugs, called kinase inhibitors, targets proteins that are critical for cancer growth and survival. However, the challenge of using these drugs effectively lies in determining which of the over 500 known kinases are most essential for tumor growth. In many human cancers, including MPNST, these data are still unavailable due to the lack of technologies needed to conduct large-scale studies of kinase function. To overcome this obstacle, our lab has developed a new and highly efficient method to identify tumor kinases and prioritize top candidates most likely to have a therapeutic benefit. Data from patient MPNST samples has deepened our understanding of the genetic changes that occur during tumor development. In addition to the NF1 gene, other genes have been identified that are commonly disrupted as tumors progress. In this study, we will model key genetic events in MPNST progression, apply our innovative approach to identify kinases involved in this process, and define how the kinases respond to potential treatment strategies. Our work will illuminate critical kinase networks in NF1-related MPNST and help identify new targets for this devastating cancer.