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

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

Blog Article

Genetic alterations that activate smashball 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 Grooming Kits 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.