The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects

Weiwei Tang (1), Ziyi Chen (2), Wenling Zhang (3), Ye Cheng (1), Betty Zhang (4), Fan Wu (1), Qian Wang (1), Shouju Wang (5), Dawei Rong (2), F. P. Reiter (6, 7), E. N. De Toni (6, 7), Xuehao Wang (2)
(1) Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
(2) Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing, China
(3) Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
(4) Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada
(5) Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
(6) Department of Medicine II, University Hospital, LMU, Munich, Germany
(7) Liver Center Munich, University Hospital, LMU, Munich, Germany

Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular carcinoma (HCC), sorafenib is currently an effective first-line therapy. Unfortunately, the development of drug resistance to sorafenib is becoming increasingly common. This study aims to identify factors contributing to resistance and ways to mitigate resistance. Recent studies have shown that epigenetics, transport processes, regulated cell death, and the tumor microenvironment are involved in the development of sorafenib resistance in HCC and subsequent HCC progression. This study summarizes discoveries achieved recently in terms of the principles of sorafenib resistance and outlines approaches suitable for improving therapeutic outcomes for HCC patients.