ABSTRACT Of the 6,500 known rare diseases, only about 5% have U.S. Food and Drug Administration-approved treatments. In cancer, rare tumors account for approximately 20% of cancer incidence but often lack established therapeutic regimens. Hence, gaining a molecular understanding of rare tumors is key for development of effective therapies. This multi-investigator proposal investigates oncogenic mutations that activate protein kinase A (PKA) to promote defective cell signaling in rare endocrine and hepatic tumors. Targeted therapeutics have transformed care for patients with rare cancers by targeting oncogenic mutations in protein kinases. PKAc-driven cancers are challenging to target in this way because this broad specificity kinase controls myriad physiological processes. Consequently, selective PKAc inhibitors have been relegated to the role of tool compounds rather than clinically viable drugs. Thus, alternative strategies must be developed to treat PKAc-driven cancers. Our preliminary profiling of oncogenic PKAc mutants provide compelling evidence that PKAc engages downstream protein kinase cascades that impact translation in adrenal and hepatic tumors. We also observed increased mRNA translation as an emerging hallmark of these PKAc driven malignancies. These findings have forged a working hypothesis that PKAc-driven cancers can be treated by targeting downstream effectors such the RNA helicase eIF4A rather than globally blocking the catalytic activity of the kinase. Three specific aims will test this transformative premise. 1) Proteomic and transcriptomic profiling of cells expressing oncogenic PKAc variants that underlie Carney complex, Cushing’s adenoma and fibrolamellar carcinoma will elucidate downstream signaling elements that impinge on mRNA translation. 2) Molecular approaches will investigate new properties imparted by the DNAJ-PKAc-chimeric kinase in fibrolamellar carcinoma that may confer resistance to chemically induced apoptosis. 3) Clinically relevant compounds and novel bivalent inhibitors will dissect the mechanism of eIF4A dependence in PKAc-driven malignancies and patient derived (PDX) models of fibrolamellar carcinoma. This proposal not only builds on a solid foundation of PKAc research, but also affords an unparalleled opportunity to discover, develop and validate drug targets for a group of patients in dire need.