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

Bryan C. Fuchs, Yujin Hoshida, Tsutomu Fujii, Lan Wei, Suguru Yamada, Gregory Y. Lauwers, Christopher M. Mcginn, Danielle K. Deperalta, Xintong Chen, Toshihiko Kuroda, Michael Lanuti, Anthony D. Schmitt, Supriya Gupta, Andrew Crenshaw, Robert Onofrio, Bradley Taylor, Wendy Winckler, Nabeel Bardeesy, Peter Caravan, Todd R. GolubKenneth K. Tanabe

Research output: Contribution to journalArticle

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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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1577-1590
Number of pages14
JournalHepatology
Volume59
Issue number4
DOIs
StatePublished - Apr 2014
Externally publishedYes

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Epidermal Growth Factor Receptor
Liver Cirrhosis
Hepatocellular Carcinoma
Fibrosis
Hepatic Stellate Cells
Transcriptome
Diethylnitrosamine
Carbon Tetrachloride
Liver
United States Food and Drug Administration
Bile Ducts
Epidermal Growth Factor
Ligation
Liver Diseases
Hepatocytes
Therapeutics
Animal Models
Phosphorylation
Pharmacology
Injections

ASJC Scopus subject areas

  • Hepatology

Cite this

Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. / Fuchs, Bryan C.; Hoshida, Yujin; Fujii, Tsutomu; Wei, Lan; Yamada, Suguru; Lauwers, Gregory Y.; Mcginn, Christopher M.; Deperalta, Danielle K.; Chen, Xintong; Kuroda, Toshihiko; Lanuti, Michael; Schmitt, Anthony D.; Gupta, Supriya; Crenshaw, Andrew; Onofrio, Robert; Taylor, Bradley; Winckler, Wendy; Bardeesy, Nabeel; Caravan, Peter; Golub, Todd R.; Tanabe, Kenneth K.

In: Hepatology, Vol. 59, No. 4, 04.2014, p. 1577-1590.

Research output: Contribution to journalArticle

Fuchs, BC, Hoshida, Y, Fujii, T, Wei, L, Yamada, S, Lauwers, GY, Mcginn, CM, Deperalta, DK, Chen, X, Kuroda, T, Lanuti, M, Schmitt, AD, Gupta, S, Crenshaw, A, Onofrio, R, Taylor, B, Winckler, W, Bardeesy, N, Caravan, P, Golub, TR & Tanabe, KK 2014, 'Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma', Hepatology, vol. 59, no. 4, pp. 1577-1590. https://doi.org/10.1002/hep.26898
Fuchs, Bryan C. ; Hoshida, Yujin ; Fujii, Tsutomu ; Wei, Lan ; Yamada, Suguru ; Lauwers, Gregory Y. ; Mcginn, Christopher M. ; Deperalta, Danielle K. ; Chen, Xintong ; Kuroda, Toshihiko ; Lanuti, Michael ; Schmitt, Anthony D. ; Gupta, Supriya ; Crenshaw, Andrew ; Onofrio, Robert ; Taylor, Bradley ; Winckler, Wendy ; Bardeesy, Nabeel ; Caravan, Peter ; Golub, Todd R. ; Tanabe, Kenneth K. / Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. In: Hepatology. 2014 ; Vol. 59, No. 4. pp. 1577-1590.
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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. Conclusion: 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.",
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AU - Hoshida, Yujin

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AU - Yamada, Suguru

AU - Lauwers, Gregory Y.

AU - Mcginn, Christopher M.

AU - Deperalta, Danielle K.

AU - Chen, Xintong

AU - Kuroda, Toshihiko

AU - Lanuti, Michael

AU - Schmitt, Anthony D.

AU - Gupta, Supriya

AU - Crenshaw, Andrew

AU - Onofrio, Robert

AU - Taylor, Bradley

AU - Winckler, Wendy

AU - Bardeesy, Nabeel

AU - Caravan, Peter

AU - Golub, Todd R.

AU - Tanabe, Kenneth K.

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