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

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.

SUBMITTER: Fuchs BC

PROVIDER: S-EPMC4086837 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Fuchs Bryan C BC Hoshida Yujin Y Fujii Tsutomu T Wei Lan L Yamada Suguru S Lauwers Gregory Y GY McGinn Christopher M CM DePeralta Danielle K DK Chen Xintong X Kuroda Toshihiko T Lanuti Michael M Schmitt Anthony D AD Gupta Supriya S Crenshaw Andrew A Onofrio Robert R Taylor Bradley B Winckler Wendy W Bardeesy Nabeel N Caravan Peter P Golub Todd R TR Tanabe Kenneth K KK

Hepatology (Baltimore, Md.) 20140228 4

<h4>Unlabelled</h4>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 ...[more]

PMID: 24677197

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Project description:PurposeSubset analyses from phase III evaluation of epidermal growth factor receptor inhibition (EGFRi) suggest improved outcomes in patients with EGFR-amplified gastroesophageal adenocarcinoma (GEA), but large-scale analyses are lacking. This multi-institutional analysis sought to determine the role of EGFRi in the largest cohort of patients with EGFR-amplified GEA to date.Patients and methodsA total of 60 patients from 15 tertiary cancer centers in six countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments-approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing, plasma circulating tumor DNA next-generation sequencing, and/or fluorescence in situ hybridization performed by a Clinical Laboratory Improvement Amendments approved laboratory. Treatment patterns and outcomes analysis was also performed using a deidentified clinicogenomic database (CGDB).ResultsSixty patients with EGFR-amplified GEA received EGFRi, including 31 of 60 patients (52%) with concurrent chemotherapy. Across treatment lines, patients achieved a 43% objective response rate with a median progression-free survival of 4.6 months (95% CI, 3.5 to 6.4). Patients receiving EGFRi in first-, second-, and third-line therapy achieved a median overall survival of 20.6 months (95% CI, 13.5 to not reached [NR]), 9 months (95% CI, 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95% CI, 8.7 to 14.2) median overall survival from first-line initiation of non-EGFRi therapy in patients with EGFR-amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011-December 2020) suggests that only 5% of patients with EGFR-amplified GEA received EGFRi.ConclusionPatients with EGFR-amplified GEA derive significant benefit from EGFRi. Further prospective investigation of EGFRi in a well-selected patient population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.

Dataset Information

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

Publications

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

Similar Datasets

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