VRK2 targeting potentiates anti-PD-1 immunotherapy in hepatocellular carcinoma through MYC destabilization

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• MYC proto-oncogene dysregulation drives hepatocellular carcinoma (HCC) but remains a challenging therapeutic target.
• Promoting MYC degradation is a promising strategy for HCC treatment.

Purpose of the Study:

• To investigate the role of vaccinia-related kinase 2 (VRK2) in MYC stabilization and its implications for HCC.
• To explore VRK2 inhibition as a therapeutic strategy for MYC-driven HCC.

Main Methods:

• Identified VRK2 as a direct MYC-interacting kinase.
• Investigated VRK2-mediated phosphorylation of MYC at Ser281/293.
• Assessed the impact of VRK2 on MYC ubiquitination and degradation by the SCF-FBXO24 E3 ligase.
• Evaluated the effect of VRK2 inhibition on HCC progression and anti-PD-1 immunotherapy in preclinical models.

Main Results:

• VRK2 directly binds and phosphorylates MYC at Ser281/293, stabilizing the oncoprotein.
• Phosphorylated MYC is protected from SCF-FBXO24-mediated ubiquitination and proteasomal degradation.
• The MYC-VRK2 complex enhances transcription of protumorigenic genes, including PD-L1 and VRK2, creating a self-reinforcing loop.
• VRK2 inhibition in HCC models decreased MYC levels, inhibited tumor growth, and synergized with anti-PD-1 therapy.

Conclusions:

• VRK2-mediated MYC stabilization is a key mechanism in hepatocarcinogenesis and immune evasion.
• Targeting VRK2 kinase activity represents a novel, mechanism-based therapeutic approach for MYC-driven HCC.
• VRK2 inhibition offers a potential strategy to overcome resistance to immunotherapy in HCC.