RAF-targeted therapy for hepatocellular carcinoma in the regenerating liver

Abstract

Background: Post-operative liver regeneration may contribute to tumor recurrence. There is a theoretical need for an adjuvant therapy that can suppress tumor growth without adversely affecting post-operative liver regeneration.

Objective: To evaluate the effect of RAF inhibitor Sorafenib on cell viability and proliferation of hepatoma cells and hepatocytes in vitro and in an in vivo rat model.

Methods: Cell viability, DNA synthesis, and RAF/MAPK kinase activity in the primary hepatocyte and hepatoma cell lines were investigated after Sorafenib exposure. Sequence analysis of the B-RAF gene in hepatic cells was determined. Tumor markers were compared within the rats after 70% hepatectomy with or without daily oral gavages of Sorafenib. Liver regeneration was assessed by liver function tests and proliferation markers.

Results: Primary hepatocytes showed higher cell viability, proliferation rate, and stronger RAF/MAPK kinase activity compared with hepatoma cell lines. The in vivo tumor volumes, size, and metastases were significantly decreased (P < 0.05) whereas no significant change in liver regeneration related to Sorafenib exposure was found (P > 0.05). B-RAF V600E mutation was not detected neither in the hepatic cells nor untransformed hepatocytes.

Conclusions: The RAF targeted inhibitor can reduce tumor growth without retarding liver regeneration in this experiment.