Background & Aims: Treatment of liver cancer remains challenging because of a paucity of drugs that target critical dependencies. Sorafenib is a multikinase inhibitor that is approved as the standard therapy for patients with advanced hepatocellular carcinoma, but it only provides limited survival benefit. In this study we aimed to identify potential combination therapies to improve the clinical response to sorafenib. Methods: To investigate the cause of the limited therapeutic effect of sorafenib, we performed a CRISPR-Cas9 based synthetic lethality screen to search for kinases whose knockout synergizes with sorafenib. Synergistic effects of sorafenib and selumetinib on cell apoptosis and phospho-ERK (p-ERK) were analyzed by caspase-3/7 apoptosis assay and western blot, respectively. p-ERK was measured by immunochemical analysis using a tissue microarray containing 78 liver cancer specimens. The in vivo effects of the combination were also measured in two xenograft models. Result: We found that suppression of ERK2 (MAPK1) sensitizes several liver cancer cell lines to sorafenib. Drugs inhibiting the MEK (MEK1/2 [MAP2K1/2]) or ERK (ERK1/2 [ MAPK1/3]) kinases reverse unresponsiveness to sorafenib in vitro and in vivo in a subset of liver cancer cell lines characterized by high levels of active p-ERK, through synergistic inhibition of ERK kinase activity. Conclusion: Our data provide a combination strategy for treating liver cancer and suggest that tumors with high basal p-ERK levels, which are seen in approximately 30% of liver cancers, are most likely to benefit from such combinatorial treatment. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
[1]Shanghai Jiao Tong Univ, Sch Med, Shanghai Canc Inst, State Key Lab Oncogenes & Related Genes,Renji Hos, Shanghai, Peoples R China;
[2]Netherlands Canc Inst, Oncode Inst, Div Mol Carcinogenesis, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands;
[3]Fudan Univ, Zhongshan Hosp, Liver Canc Inst, Key Lab Carcinogenesis & Canc Invas,Minist Educ, Shanghai, Peoples R China;
[4]Second Mil Med Univ, Eastern Hepatobiliary Surg Hosp, Dept Pathol, Shanghai, Peoples R China
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