Abstract 2925: Gene expression analysis to monitor erlotinib prevention of hepatocellular transformation during cirrhosis
Authors: Bryan C. Fuchs, Yujin Hoshida, Tsutomu Fujii, Gregory Y. Lauwers, Christopher M. McGinn, Suguru Yamada, Toshihiko Kuroda, Michael Lanuti, Supriya Gupta, Andrew Crenshaw, Robert Onofrio, Bradley Taylor, Wendy Winckler, Todd R. Golub, Kenneth K. Tanabe
Journal: Cancer Research (2010)

Abstract 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&amp;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.