Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma.

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Title: Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma.
Authors: Pinato, D
Brown, MW
Trousil, S
Aboagye, E
Beaumont, J
Zhang, H
Coley, HM
Mauri, F
Sharma, R
Item Type: Journal Article
Abstract: Background: Aberrant activation of Axl is implicated in the progression of HCC. We explored biologic significance and preclinical efficacy of Axl inhibition as a therapeutic strategy in sorafenib-naïve and resistant HCC. Methods: We evaluated Axl expression in sorafenib-naïve and resistant (SR) clones of epithelial (HuH7) and mesenchymal origin (SKHep-1) using antibody arrays and confirmed tissue expression. We tested the effect of Axl inhibition with RNA-interference and pharmacologically with R428 on a number of phenotypic assays. Results: Axl mRNA overexpression in cell lines (n=28) and RNA-seq tissue datasets (n=373) correlated with epithelial-to-mesenchymal transition (EMT). Axl was overexpressed in HCC compared to cirrhosis and normal liver. We confirmed sorafenib-resistance to be associated with EMT and enhanced motility in both HuH7-SR and SKHep-1-SR cells documenting a 4-fold increase in Axl phosphorylation as an adaptive feature of chronic sorafenib treatment in SKHep-1-SR cells. Axl inhibition reduced motility and enhanced sensitivity to sorafenib in SKHep-1SR cells. In patients treated with sorafenib (n=40) circulating Axl levels correlated with shorter survival. Conclusions: Suppression of Axl-dependent signaling influences the transformed phenotype in HCC cells and contributes to adaptive resistance to sorafenib, providing a pre-clinical rationale for the development of Axl inhibitors as a measure to overcome sorafenib resistance.
Issue Date: 15-Feb-2019
Date of Acceptance: 27-Nov-2018
URI: http://hdl.handle.net/10044/1/66537
ISSN: 0007-0920
Publisher: Springer Nature [academic journals on nature.com]
Journal / Book Title: British Journal of Cancer
Copyright Statement: This paper is embargoed until publication. Once published it will be available fully open access.
Sponsor/Funder: The Academy of Medical Sciences
Funder's Grant Number: N/A
Keywords: 1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Accepted
Embargo Date: publication subject to indefinite embargo
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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