Z Gastroenterol 2013; 51 - P_4_28
DOI: 10.1055/s-0032-1332073

Effects of the mTOR inhibitor RAD001, the dual mTOR and PI3-kinase inhibitor BEZ235 and the PI3-kinase inhibitor BKM120 on HCC

MM Kirstein 1, AE Boukouris 1, D Pothiraju 1, LE Buitrago-Molina 1, S Marhenke 1, J Orlik 1, MP Manns 1, A Vogel 1
  • 1Hannover Medical School, Gastroenterology, Hepatology & Endocrinology, Hannover, Germany

Introduction: Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide with only few therapeutic options for patients with advanced disease. Aberrant mTOR signaling has been identified in up to 50–60% of cases of hepatocellular carcinoma and therefore represents a promising target for novel therapeutic approaches. This study evaluated the anti-tumor effect of the mTOR inhibitor RAD001, the dual PI3-kinase and mTOR inhibitor BEZ235 and the PI3-kinase inhibitor BKM120 in human hepatoma cell lines in vitro and in a HCC xenograft mouse model.

Experimental Design: The anti-tumor effects of RAD001, BEZ235 and BKM120 were analysed in seven hepatoma cell lines as mono and combination therapy with Doxorubicin, Cisplatin, Irinotecan or 5-Flourouracil in vitro and in Huh7 xenografts. Cell-cycle progression and apoptosis were analysed. Furthermore, effects on mitochondrial respiration and glycolysis were assessed.

Results: BKM120 showed a higher anti-tumor activity compared to RAD001 and BEZ235. Interestingly, all drugs impaired tumor growth mainly by inhibiting cell-cycle progression and impairment of mitochondrial function than by inducing apoptosis. BKM120, which exhibited the strongest anti-proliferative effect, most significantly impaired oxidative phosphorylation compared to the other drugs. Additionally, combination treatment with cytotoxic agent such as Cisplatin exhibited a strong synergistic effect.

Conclusions: BKM120 showed a higher anti-tumor activity compared to RAD001 and BEZ235. Interestingly, all drugs impaired tumor growth mainly by inhibiting tumor cell proliferation and impairment of mitochondrial function. Interestingly, the efficacy did not correlate with AKT, 4E-BP1 or S6 activation. Additionally, combination treatment with cytotoxic agent such as Cisplatin exhibited a strong synergistic effect. These preclinical results provide therefore a rationale to test mTOR and PI3-kinase inhibitors in combination with chemotherapy in non-cirrhotic HCC patients that tolerate chemotherapy.