Torin2 overcomes sorafenib resistance via suppressing mTORC2-AKT-BAD pathway in hepatocellular carcinoma cells.

BACKGROUND: Sorafenib is an oral multi-kinase inhibitor that was approved by the US Food and Drug Administration for the treatment of patients with advanced hepatocellular carcinoma (HCC). However, resistance to sorafenib is an urgent problem to be resolved to improve the therapeutic efficacy of sorafenib. As the activation of AKT/mTOR played a pivotal role in sorafenib resistance, we evaluated the effect of a dual mTOR complex 1/2 inhibitor Torin2 on overcoming the sorafenib resistance in HCC cells. METHODS: The sorafenib-resistant Huh7 and Hep3B cell lines were established from their parental cell lines. The synergistic effect of sorafenib and Torin2 on these cells was measured by cell viability assay and quantified using the Chou-Talalay method. Apoptosis induced by the combination of sorafenib and Torin2 and the alteration in the specific signaling pathways of interest were detected by Western blotting. RESULTS: Sorafenib treatment inversely inhibited AKT in parental but activated AKT in sorafenib-resistant Huh7 and Hep3B HCC cells, which underscores the significance of AKT activation. Torin2 and sorafenib synergistically suppressed the viability of sorafenib-resistant cells via apoptosis induction. Torin2 successfully suppressed the sorafenib-activated mTORC2-AKT axis, leading to the dephosphorylation of Ser136 in BAD protein, and increased the expression of total BAD, which contributed to the apoptosis in sorafenib-resistant HCC cells. CONCLUSIONS: In this study, Torin2 and sorafenib showed synergistic cytostatic capacity in sorafenib-resistant HCC cells, via the suppression of mTORC2-AKT-BAD pathway. Our results suggest a novel strategy of drug combination for overcoming sorafenib resistance in HCC.

Interferon and lamivudine combination therapy versus lamivudine monotherapy for hepatitis B e antigen-negative hepatitis B treatment: a meta-analysis of randomized controlled trials.

BACKGROUND: It has been demonstrated that only a minority of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) obtain a sustained response after either interferon (IFN) or nucleos(t)ide analogue monotherapy. Therefore, combination therapy of drugs with synergistic antiviral effects was proposed to have a sustained response in these patients. We compared the effect and safety of lamivudine monotherapy and its combination with IFN including conventional interferon (CON-IFN) and pegylated interferon (PEG-IFN) for HBeAg-negative CHB patients. DATA SOURCES: A group of three independent reviewers identified 9 eligible randomized controlled trials through electronic searches (MEDLINE, OVID, EMBASE, the Cochrane Library Clinical Trials Registry, and the Chinese Medical Database), manual searches, and contact with experts. Sustained virological and biochemical responses were defined as primary efficacy measures. We performed quantitative meta-analyses to assess differences between CON-IFN plus lamivudine combination and lamivudine monotherapy groups. RESULTS: No greater sustained virological and biochemical rates were found in patients receiving CON-IFN/lamivudine combination therapy [29.1% vs. 26.7%, odds ratio (OR)=0.98, 95% confidence interval (CI) 0.65-1.50, P=0.94, and 41.8% vs. 40.3%, OR=1.13, 95% CI 0.78-1.65, P=0.51, respectively], though a reduced YMDD mutation rate was achieved in the combination group [8.39% vs. 30.0%, OR=0.16, 95% CI 0.076-0.33, P<0.001]. However, data from one PEG-IFN trial showed greater sustained virological and biochemical rates in patients receiving combination therapy [response rate 19.5% vs. 6.6%, OR=3.42, 95% CI 1.71-6.84, P<0.001 and 60.0% vs. 44.2%, OR=1.88, 95% CI 1.23-2.85, P=0.003, respectively]. CONCLUSIONS: Addition of CON-IFN to lamivudine did not improve treatment efficacy but suppressed YMDD mutation by lamivudine. Combination of PEG-IFN and lamivudine might increase the sustained response, and further clinical trials are needed for confirmation.