HEPATITIS B VIRUS ANTAGONIZES SORAFENIB IN HEPATOMA CELLS THROUGH INDIRECT INDUCTION OF THE RAF-MEK-ERK PATHWAY

Hepatitis B virus (HBV) is a small DNA virus that targets the liver and is a major driver for end-stage liver disease and liver cancer. As an oncogenic virus, HBV not only promotes malignant transformation of the liver but may also confer resistance to available molecularly targeted anti-cancer drug therapy, the multi-kinase inhibitor sorafenib.

Our results show that HepG2.2.15 hepatoma cells that stably express HBV are less susceptible to sorafenib pro-apoptotic effect as compared to HBV-null cells. This effect is HBV-dependent, since the same cell line in which HBV expression was knocked out presented reversibility of the sorafenib-resistance effect. To gain more insight into molecular pathways implicated in HBV-associated resistance to sorafenib and given that the Raf-Mek-Erk pathway is one of the major pathways blocked by sorafenib, we analyzed the activation state of this pathway in the presence or in the absence of HBV. To our surprise, we revealed enhanced basal activation of phosphorylated Erk (pErk). This activation was HBV dependent and was maintained even in the presence of sorafenib that blocks the upstream Raf protein kinase. In addition, enhanced HBV dependent activation of p70S6K, which is downstream of mTOR signaling and aberrantly activated in 50% of HCC cases has been observed even upon sorafenib treatment. Conclusions: HBV confers relative resistance to sorafenib treatment and this is associated with indirect activation of the Raf-Mek-Erk and mTOR pathways. Our findings suggest that the addition of mTOR inhibitors, such as evarolimus, to sorafenib may have an additive anti-HCC effect over sorafenib mono therapy, especially among patients with HBV-associated liver cancer.