Erlotinib and sorafenib in an orthotopic rat model of hepatocellular carcinoma.
OBJECTIVE
The combination of erlotinib with sorafenib is currently being investigated in a phase III RCT. We studied the effect of erlotinib and sorafenib on HCC in a preclinical model.


METHODS
The Morris Hepatoma (MH) and HepG2 cells were treated in vitro with sorafenib (1-10 μM) and erlotinib (1-5 μM) and evaluated for tumor cell viability, apoptosis, and target regulation. Antiangiogenic effects were studied by measuring VEGF levels, endothelial cell viability, apoptosis, migration, and the aortic ring assay. In vivo, MH cells were implanted into the liver of syngeneic rats and treated with vehicle, sorafenib 5-10mg/kg, erlotinib 10mg/kg, and respective combinations.


RESULTS
In vitro, erlotinib downregulated p-ERK but showed no significant effect on tumor cell viability in MH and HEPG2 cells. Despite a similar target regulation, sorafenib significantly reduced cell viability of HCC cells by induction of apoptosis, in a dose-dependent manner (11 ± 5%; 20 ± 10%; 51 ± 5% for sorafenib 1, 5, 10 μM). No additional effect was observed upon combination with erlotinib. Of note, erlotinib treatment resulted in endothelial cell migration and vascular sprouting of aortic rings through induction of VEGF mRNA and protein levels in endothelial and tumor cells, which was blocked by sorafenib. In vivo, erlotinib had no single agent antitumor activity, raised serum-VEGF levels, and lacked a synergistic effect in combination with sorafenib.


CONCLUSIONS
Erlotinib had no antitumor effect on HCC in vitro nor in vivo, but induced VEGF, which may reflect a resistance mechanism to erlotinib monotherapy. No improvement of sorafenib efficacy was observed upon combination with erlotinib.
Department of Internal Medicine III, Division of Gastroenterology/Hepatology and Comprehensive Cancer Center, Medical University Vienna, Austria.
Wolfgang
W
Sieghart
Matthias
M
Pinter
Bernhard
B
Dauser
Natalya
N
Rohr-Udilova
Anne-Christine
AC
Piguet
Gerald
G
Prager
Hubert
H
Hayden
Hans-Peter
HP
Dienes
Jean-Francois
JF
Dufour
Markus
M
Peck-Radosavljevic
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors