Transl Oncol. 2018 Mar 7;11(2):511-517. doi: 10.1016/j.tranon.2018.02.015. [Epub ahead of print]
Inhibition of pMAPK14 Overcomes Resistance to Sorafenib in Hepatoma Cells with Hepatitis B Virus.
Witt-Kehati D1, Fridkin A2, Alaluf MB3, Zemel R1, Shlomai A4.
Author information
1
Felsenstein Medical Research Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
2
Department of Medicine D, Beilinson hospital Rabin Medical Center, Petah-Tikva, Israel.
3
Felsenstein Medical Research Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Medicine D, Beilinson hospital Rabin Medical Center, Petah-Tikva, Israel.
4
Felsenstein Medical Research Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Medicine D, Beilinson hospital Rabin Medical Center, Petah-Tikva, Israel; The Liver Institute, Beilinson Hospital Rabin Medical Center, Petah-Tikva, Israel. Electronic address: [email protected].
Abstract
Hepatitis B virus (HBV) targets the liver and is a major driver for liver cancer. Clinical data suggest that HBV infection is associated with reduced response to treatment with the multi-kinase inhibitor sorafenib, the first available molecularly targeted anti-hepatocellular carcinoma (HCC) drug. Given that Raf is one of the major targets of sorafenib, we investigated the activation state of the Raf-Mek-Erk pathway in the presence of HBV and in response to sorafenib. Here we show that hepatoma cells with replicating HBV are less susceptible to sorafenib inhibitory effect as compared to cells in which HBV expression is suppressed. However, although HBV replication is associated with increased level of pErk, its blockade only modestly augments sorafenib effect. In contrast, the phosphorylated form of the pro-oncogenic Mitogen-Activated Protein Kinase 14 (pMAPK14), a protein kinase that was recently linked to sorafenib resistance, is induced in sorafenib-treated hepatoma cells in association with HBV X protein expression. Knocking down pMAPK14 results in augmentation of the therapeutic efficacy of sorafenib and largely alleviates resistance to sorafenib in the presence of HBV. Thus, this study suggests that HBV promotes HCC resistance to sorafenib. Combining pMAPK14 inhibitors with sorafenib may be beneficial in patients with HBV-associated HCC.