Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma

TLDR

Hepatocellular carcinoma is the fastest growing cause of cancer death in the U.S., and because few therapies exist, prevention in high‑risk cirrhotic patients—where EGF signaling drives disease progression—is a priority. The study aimed to test whether the EGFR inhibitor erlotinib could reduce liver fibrosis and prevent HCC in animal models of progressive cirrhosis. Erlotinib was administered to rats and mice with diethylnitrosamine, carbon tetrachloride, or bile duct ligation‑induced cirrhosis to inhibit EGFR signaling in hepatic stellate cells and hepatocytes. Treatment lowered EGFR phosphorylation, decreased activated stellate cells, reduced hepatocyte proliferation and liver injury, regressed fibrosis, and blocked HCC development, with efficacy trackable by a gene‑expression signature.

Abstract

Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer-related mortality in the United States. Because of the lack of viable treatment options for HCC, prevention in high-risk patients has been proposed as an alternative strategy. The main risk factor for HCC is cirrhosis and several lines of evidence implicate epidermal growth factor (EGF) in the progression of cirrhosis and development of HCC. We therefore examined the effects of the EGF receptor (EGFR) inhibitor erlotinib on liver fibrogenesis and hepatocellular transformation in three different animal models of progressive cirrhosis: a rat model induced by repeated, low-dose injections of diethylnitrosamine (DEN), a mouse model induced by carbon tetrachloride (CCl4 ), and a rat model induced by bile duct ligation (BDL). Erlotinib reduced EGFR phosphorylation in hepatic stellate cells (HSC) and reduced the total number of activated HSC. Erlotinib also decreased hepatocyte proliferation and liver injury. Consistent with all these findings, pharmacological inhibition of EGFR signaling effectively prevented the progression of cirrhosis and regressed fibrosis in some animals. Moreover, by alleviating the underlying liver disease, erlotinib blocked the development of HCC and its therapeutic efficacy could be monitored with a previously reported gene expression signature predictive of HCC risk in human cirrhosis patients. These data suggest that EGFR inhibition using Food and Drug Administration-approved inhibitors provides a promising therapeutic approach for reduction of fibrogenesis and prevention of HCC in high-risk cirrhosis patients who can be identified and monitored by gene expression signatures.