Abstract 2925: Gene expression analysis to monitor erlotinib prevention of hepatocellular transformation during cirrhosis
Authors: Fuchs Bryan C. , Hoshida Yujin , Fujii Tsutomu , Lauwers Gregory Y. , McGinn Christopher M. , Yamada Suguru , Kuroda Toshihiko , Lanuti Michael , Gupta Supriya , Crenshaw Andrew , Onofrio Robert , Taylor Bradley , Winckler Wendy , Golub Todd R. , Tanabe Kenneth K. 
Published: February 2011

Background: Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and due to its poor prognosis it is the third leading cause of cancer-related death. Given the lack of successful treatment options, chemoprevention in high-risk patients has been proposed as an alternative strategy. Mounting evidence supports a role for epidermal growth factor (EGF) during chronic liver disease and hepatocellular transformation. Based on these findings, we address the hypothesis that blocking the EGF-EGF receptor (EGFR) pathway may be an effective strategy for inhibiting fibrogenesis and hepatocarcinogenesis. Methods: A rat model of diethylnitrosamine (DEN)-induced cirrhosis was used to examine the effects of erlotinib on underlying chronic liver disease and HCC formation. DEN (50 mg/kg) was administered weekly throughout the study while erlotinib (either 0.5 or 2 mg/kg) was administered 5 days per week for 6 weeks beginning at the onset of cirrhosis. At the end of the study, rats were sacrificed and tumor nodules were counted. Disease progression was assessed by H&E and trichrome staining. The effects of erlotinib on EGFR signaling were examined by western blot analysis. Activation of hepatic stellate cells was assessed by alpha-smooth muscle actin staining and blood tests were performed to determine hepatotoxicity and overall liver function. Finally, genome-wide gene expression profiling was used to compare the similarities between rat cirrhosis and human cirrhosis as well as to monitor the response to erlotinib. Results: The DEN-induced rat model closely resembles disease progression in humans. Liver fibrosis and cirrhosis were pathologically observed after 8 and 12 weeks, respectively, and multiple well-differentiated HCCs formed only in cirrhotic livers after 18 weeks. Microarray analysis revealed that DEN-induced rat cirrhosis recapitulates genome-wide gene expression observed in human cirrhosis. Erlotinib significantly prevented the development of HCC tumor nodules in a dose-dependent fashion. Erlotinib was shown to inhibit EGFR signaling more profoundly in the surrounding non-tumoral tissue than in residual tumors. Further, erlotinib inhibited the activation of hepatic stellate cells and prevented fibrogenesis. Erlotinib also reduced hepatotoxicity and improved liver function. Finally, a gene expression signature predictive of poor survival in human cirrhosis patients was reversed in response to erlotinib. Conclusions: Our data demonstrate for the first time that EGFR inhibition prevents liver fibrogenesis. Further, our results suggest that erlotinib is a potentially effective HCC chemoprevention agent that prevents progression of cirrhosis and its effects can be monitored using gene expression signatures.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2925.