Background: Hepatocellular carcinoma (HCC) is a particularly vascularized solid tumor and the Raf/MEK/ERK pathway is activated in HCC. Sorafenib has been shown to prolong survival of patients with advanced HCC. BAY 86-9766 (RDEA119) is an orally available, potent, allosteric MEK inhibitor currently in Phase I/II trials. A combination therapy of MEK inhibitor BAY 86-9766 with sorafenib might enhance the therapeutic efficacy of sorafenib in HCC. This study aims to investigate the potential of such a combined therapeutic approach in preclinical models of HCC.

Methods: We treated 15 patient-derived HCC xenograft models (Asian origin) with i) sorafenib, ii) BAY 86-9766, and iii) sorafenib plus BAY 86-9766. Western blotting was employed to determine pharmacodynamic changes in biomarkers relevant to both angiogenesis and MEK signaling. Apoptosis, microvessel density, and cell proliferation were analyzed by immunohistochemistry.

Results: We report here that sorafenib significantly suppressed tumor growth with the T/C ratios ranging from 0.25 to 0.6, angiogenesis and cell proliferation with modest elevation of pERK Thr202/Tyr204. BAY 86-9766 treatment caused a modest tumor growth inhibition (ranging from 30 to 60%) and dephosphorylation of ERK, Bim and p90RSK. The addition of BAY 86-9766 to sorafenib significantly augmented the antitumor activity of sorafenib in 15 models of HCC. The T/C ratios for the sorafenib/BAY 86-9766 ranged from 0.03 to 0.2. Such inhibition led to further increase in Bad, Bim and apoptosis. Profound inhibition of cell proliferation, angiogenesis and inactivation of p90RSK and mTOR targets were also observed in the combined therapy.

Conclusion: We show that sorafenib/BAY 86-9766 treatment is considerably more effective than either single agents in suppressing tumor growth, angiogenesis, cell proliferation and cell survival. Our findings underscore the potential of sorafenib/BAY 86-9766 combination in the treatment of HCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B3.