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

[Display omitted] •ERK2 inhibition was identified as an enhancer of the response to sorafenib in HCC.•Selumetinib increases the response of sorafenib in HCC cell lines with high p-ERK.•The synthetic lethal effect is derived from synergistic inhibition of ERK kinase.•The combination therapy is most l...

Full description

Saved in:
Bibliographic Details
Published in:Journal of hepatology Vol. 69; no. 5; pp. 1057 - 1065
Main Authors: Wang, Cun, Jin, Haojie, Gao, Dongmei, Lieftink, Cor, Evers, Bastiaan, Jin, Guangzhi, Xue, Zheng, Wang, Liqin, Beijersbergen, Roderick L., Qin, Wenxin, Bernards, René
Format: Journal Article
Language:English
Published: Netherlands Elsevier B.V 01.11.2018
Elsevier Science Ltd
Subjects:
Apoptosis
Biomarkers
Caspase
Caspase-3
Clinical outcomes
CRISPR
CRISPR screen
Drug therapy
Extracellular signal-regulated kinase
Hepatocellular carcinoma
Hepatocytes
Inhibitor drugs
Lethality
Liver cancer
MAPK1
MEK inhibitors
Patients
Sorafenib
Tumor cell lines
Tumors
Xenografts
Hepatocellular carcinoma
CRISPR screen
MAPK1
Sorafenib
ISSN:0168-8278, 1600-0641, 1600-0641
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] •ERK2 inhibition was identified as an enhancer of the response to sorafenib in HCC.•Selumetinib increases the response of sorafenib in HCC cell lines with high p-ERK.•The synthetic lethal effect is derived from synergistic inhibition of ERK kinase.•The combination therapy is most likely to be effective in tumors with high p-ERK. 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 characterized by high levels of active p-ERK, through synergistic inhibition of ERK kinase activity. 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. Sorafenib is approved as the standard therapy for patients with advanced hepatocellular carcinoma, but only provides limited survival benefit. Herein, we found that inhibition of the kinase ERK2 increases the response to sorafenib in liver cancer. Our data indicate that a combination of sorafenib and a MEK inhibitor is most likely to be effective in tumors with high basal phospho-ERK levels.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:0168-8278
1600-0641
1600-0641
DOI:10.1016/j.jhep.2018.07.004