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EGF receptor inhibitors comprehensively suppress hepatitis B virus by downregulation of STAT3 phosphorylation

Chong J Gan1, Wen F Li1, Chun N Li1

  • 1Center of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, 519000, China.

Biochemistry and Biophysics Reports
|April 24, 2020
PubMed

Insights

Epidermal growth factor receptor (EGFR) inhibitors like erlotinib show promise in combating chronic hepatitis B virus (HBV) infection by reducing viral replication and antigens. Extended treatment duration enhances these significant anti-HBV effects.

Area of Science:

  • Hepatology and Virology
  • Drug Discovery and Development

Background:

  • Current therapies for chronic hepatitis B virus (HBV) infection are insufficient for a cure or to eliminate hepatocellular carcinoma risk.
  • Epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy against hepatitis C virus (HCV) by downregulating signal transducers and activators of transcription 3 (STAT3) phosphorylation.
  • STAT3 plays a role in HBV replication, suggesting EGFR inhibitors as potential anti-HBV agents.

Purpose of the Study:

  • To investigate the anti-HBV efficacy of EGFR inhibitors erlotinib and gefitinib.
  • To evaluate the impact of these inhibitors on HBV replication, viral antigen synthesis, and the covalently closed circular DNA (cccDNA) reservoir.
  • To explore the underlying mechanisms and potential for enhanced therapeutic effects with extended treatment duration.

Main Methods:

  • Utilized HBV-transfected HepG2.2.15 cells and HBV-infected HepG2-NTCP cells as experimental models.
  • Assessed HBV replication, viral antigen synthesis (including hepatitis B e antigen), and cccDNA levels as key indicators of anti-HBV activity.
  • Determined half-maximal inhibitory concentrations (IC50) for erlotinib and gefitinib and investigated mechanisms involving STAT3 phosphorylation and suppressor of cytokine signaling 3.

Main Results:

  • Erlotinib demonstrated significant inhibition of HBV replication (IC50 = 1.05 μM) and reduced viral antigen synthesis at concentrations ≥ 2.5 μM.
  • Gefitinib also exhibited anti-HBV activity, inhibiting replication and antigen production.
  • Both EGFR inhibitors reduced hepatitis B e antigen levels compared to entecavir; erlotinib showed a marginal reduction in the cccDNA reservoir.
  • Anti-HBV effects were notably enhanced with prolonged treatment duration.

Conclusions:

  • EGFR inhibitors erlotinib and gefitinib display comprehensive potential as novel therapeutic agents against HBV infection.
  • The mechanism may involve the inhibition of STAT3 phosphorylation, potentially through the upregulation of suppressor of cytokine signaling 3.
  • These findings suggest a promising new strategy for curing HBV infection, warranting further investigation in animal models and clinical trials.
Keywords:
Antiviral therapyCovalently closed circular DNAEGF, epidermal growth factorEGFR, epidermal growth factor inhibitorEpidermal growth factor receptor inhibitorGEq, genome equivalentHBV, hepatitis B virusHBeAg, hepatitis B e antigenHBsAg, hepatitis B surface antigenHCC, hepatocellular carcinomaHNF3, hepatocyte nuclear factor 3Hepatitis B virusIFN, interferonMTT, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromideNAs, nucleotide/nucleoside analoguesNTCP, sodium taurocholate cotransporting polypeptidePCR, polymerase chain reactionSOCS3, suppressor of cytokine signaling 3STAT3STAT3, signal transduction and activators of transcription 3cccDNA, covalently closed circular DNA

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