Sorafenib resistance and autophagy in hepatocellular carcinoma: A concealed threat

Abstract

Objective: To investigate the relationship between sorafenib resistance and autophagy in hepatocellular carcinoma (HCC). Data Sources: Literature from PubMed (ncbi) database relevant to autophagy and sorafenib resistance in HCC. Study Selection: Studies were selected based on their experimental and observational nature with regards to autophagy and sorafenib resistance in HCC. Observational human studies and sorafenib clinical trials were selected to analyze the epidemiology of HCC, pharmacological properties of sorafenib, autophagy in human HCC, sorafenib treatment in humans, and sorafenib resistance in HCC. In-vivo and In-vitro preclinical studies were selected to analyze the effect of sorafenib on autophagy in HCC and the effect of sorafenib-induced autophagy in HCC. Results: Sorafenib blocked the Akt/mTOR and MEK/ERK pathways which are downstream of ras/raf signaling. By blocking these pathways, sorafenib altered autophagic regulatory signaling pathways, thereby initiating autophagy as a collateral effect. In addition, sorafenib paradoxically activated AMPK, thereby initiating autophagy in human HCC cells. Sorafenib also increased autophagy by upregulating pro-autophagic proteins such as beclin-1, Atg5, LC3II and Vps34. Sorafenib resistance developed in HCC as a consequence of autophagy. Conclusion: Autophagy induced by sorafenib could be a mechanism for the development of sorafenib resistance in HCC.