Phospho-ERK is a biomarker of response to a synthetic lethal drug combination of sorafenib and MEK inhibition in liver cancer

Journal of Hepatology
Cun WangRene Bernards

Abstract

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. 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. 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 characteri...Continue Reading

Citations

Jan 23, 2019·Daru : Journal of Faculty of Pharmacy, Tehran University of Medical Sciences·Ali SaberHidde J Haisma
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