Ibrutinib and sorafenib synergistically inhibit HCC growth in preclinical models

Hepatocellular carcinoma (HCC) is the second major cause of cancer-related death worldwide with limit therapeutic options. Thus, there is an urgent need to develop novel alternative therapies for HCC. In this study, we report that ibrutinib, recently approved for the treatment of B cell malignancies, and a covalent inhibitor of TEC (BTK, ITK etc.) and ERBB (EGFR, Her2 etc.) family of tyrosine kinases, inhibits tumorigenic functions of human HCC cells in vitro and in xenografts. More importantly, co-treatment with ibrutinib and sorafenib, an approved targeted therapy for advanced HCCs that marginally improve patients9 survival, synergistically inhibited proliferation and clonogenic survival of HCC cells including those with acquired sorafenib resistance. Mechanistically, ibrutinib inhibits Akt and ERK signaling pathways through inactivating EGFR, its irreversible substrate in HCC cells. Besides, tumor sphere formation and expression of cancer stem cell markers were suppressed by ibrutinib and sorafenib co-treatment in HCC cells. Ectopic expression of the constitutively active Akt mutant abrogated the synergism of these two kinase inhibitors on HCC cell survival. Ibrutinib and sorafenib combination therapy significantly suppressed tumor growth of highly aggressive HCCLM3 subcutaneous xenografts in NSG mice. Collectively, these results demonstrate that ibrutinib could be a re-purposed anti-HCC drug, and our data provides the evidence for the therapeutic potential of ibrutinib and sorafenib combination as an effective and attractive strategy for treating HCCs including those with sorafenib resistance. Citation Format: Kalpana Ghoshal, Cho-hao Lin, Khadija Elkholy, Nissar A. Wani, Ding Li, Juan M. Barajas, Peng Hu, Xiaoli Zhang, Lianbo Yu, Tasneem Motiwala. Ibrutinib and sorafenib synergistically inhibit HCC growth in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3470.