Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms

Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. Yet, their downstream oncogenic signaling mechanisms are poorly understood. We used global phosphoproteomics and kinase activity profiling to map conserved signaling outputs driven by a range of genetic changes that activate PKA in human cancer. Two signaling networks were identified downstream of PKA: RAS/MAPK components and an Aurora Kinase A (AURKA)/glycogen synthase kinase (GSK3) sub-network with activity toward MYC oncoproteins. Findings were validated in two PKA-dependent cancer models: a novel, patient-derived fibrolamellar carcinoma (FLC) line that expresses a DNAJ-PKAc fusion and a PKA-addicted melanoma model with a mutant type I PKA regulatory subunit. We identify PKA signals that can influence both de novo translation and stability of the proto-oncogene c-MYC. However, the primary mechanism of PKA effects on MYC in our cell models was translation and could be blocked with the eIF4A inhibitor zotatifin. This compound dramatically reduced c-MYC expression and inhibited FLC cell line growth in vitro. Thus, targeting PKA effects on translation is a potential treatment strategy for FLC and other PKA-driven cancers.

Automated summary

Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. The downstream oncogenic signaling mechanisms of PKA activation in human cancer were explored using phosphoproteomics and kinase activity profiling. Two signaling networks, RAS/MAPK components and an AURKA/GSK3 sub-network, were identified, both affecting MYC oncoproteins. Primary mechanism of PKA effects on MYC was found to be translation, which could be blocked with the eIF4A inhibitor zotatifin, suggesting a potential treatment strategy for PKA-driven cancers.