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

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Genetic alterations activating protein kinase A (PKA) are implicated in numerous cancers.
• The specific downstream signaling pathways driving oncogenesis by PKA remain incompletely understood.

Purpose of the Study:

• To elucidate the conserved signaling networks regulated by PKA activation in human cancers.
• To investigate the role of PKA in regulating the proto-oncogene c-MYC and its therapeutic implications.

Main Methods:

• Global phosphoproteomics and kinase activity profiling were employed to map PKA-driven signaling.
• PKA-dependent cancer models, including fibrolamellar carcinoma (FLC) and melanoma, were utilized for validation.
• The effects of PKA on c-MYC translation and stability were assessed, along with the impact of the eIF4A inhibitor zotatifin.

Main Results:

• Two key signaling networks downstream of PKA were identified: RAS/MAPK and an Aurora Kinase A (AURKA)/glycogen synthase kinase (GSK3) sub-network targeting MYC.
• PKA influences both de novo translation and stability of c-MYC, with translation being the predominant mechanism in tested models.
• The eIF4A inhibitor zotatifin effectively blocked PKA's effects on MYC translation, significantly reducing c-MYC expression and inhibiting FLC cell growth.

Conclusions:

• PKA activation in cancer converges on specific signaling networks, including those regulating MYC.
• Targeting PKA's influence on c-MYC translation presents a promising therapeutic strategy for fibrolamellar carcinoma and other PKA-driven malignancies.
• The eIF4A inhibitor zotatifin demonstrates potential for treating cancers driven by PKA signaling.