The Epidermal Growth Factor Receptor (EGFR) Inhibitor Gefitinib Reduces but Does Not Prevent Tumorigenesis in Chemical and Hormonal Induced Hepatocarcinogenesis Rat Models.

Silvia Ribback,Julia Günther,Matthias Evert,Maria Pilo,Enrico Böhning,Antonio Cigliano,Frauke Steinmüller,Jaqueline Merz,Frank Dombrowski,Kirsten Utpatel,Verena Sailer,Kristin Peters,Diego Calvisi

doi:10.3390/ijms17101618

Abstract

Activation of the epidermal growth factor receptor (EGFR) signaling pathway promotes the development of hepatocellular adenoma (HCA) and carcinoma (HCC). The selective EGFR inhibitor Gefitinib was found to prevent hepatocarcinogenesis in rat cirrhotic livers. Thus, Gefitinib might reduce progression of pre-neoplastic liver lesions to HCC. In short- and long-term experiments, administration of N-Nitrosomorpholine (NNM) or intrahepatic transplantation of pancreatic islets in diabetic (PTx), thyroid follicles in thyroidectomized (TTx) and ovarian fragments in ovariectomized (OTx) rats was conducted for the induction of foci of altered hepatocytes (FAH). Gefitinib was administered for two weeks (20 mg/kg) or three and nine months (10 mg/kg). In NNM-treated rats, Gefitinib administration decreased the amount of FAH when compared to controls. The amount of HCA and HCC was decreased, but development was not prevented. Upon all transplantation models, proliferative activity of FAH was lower after administration of Gefitinib in short-term experiments. Nevertheless, the burden of HCA and HCC was not changed in later stages. Thus, EGFR inhibition by Gefitinib diminishes chemical and hormonal also induced hepatocarcinogenesis in the initiation stage in the non-cirrhotic liver. However, progression to malignant hepatocellular tumors was not prevented, indicating only a limited relevance of the EGFR signaling cascade in later stages of hepatocarcinogenesis.

Highlights

Hepatocellular carcinoma (HCC) is the fifth leading cause of tumor related deaths worldwide with increasing incidence in the Western hemisphere [1]
Partial resection and liver transplantation remain the only curative options, but most cases of HCC are diagnosed in an advanced stage and are not suitable for surgical therapy
epidermal growth factor receptor (EGFR) is expressed in most HCC [10,27], and EGFR inhibitors such as the monoclonal antibody cetuximab or tyrosine kinase inhibitors such as Gefitinib and Erlotinib are able to suppress HCC growth both in vitro and in vivo [9,28,29]

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth leading cause of tumor related deaths worldwide with increasing incidence in the Western hemisphere [1]. The prognosis and overall survival of HCC patients is poor, with less than 5% five-year survival. Partial resection and liver transplantation remain the only curative options, but most cases of HCC are diagnosed in an advanced stage and are not suitable for surgical therapy. Ablation therapies, including radio-frequency ablation, transarterial chemoembolization, and radioembolization are effective in slowing tumor progression in advanced stages [4]. Sorafenib (Nexavar©, Bayer, Karlsruhe, Germany) was the first (and still the only one) of this class of new drugs to be approved by the Food and Drug Administration for the treatment of HCC, as overall survival was improved [6]

Results

Discussion

Conclusion