Imperial College London
Alternate

ProfessorEricAboagye

Faculty of Medicine, Department of Surgery & Cancer

Professor
 
 
 
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Contact

 

+44 (0)20 3313 3759eric.aboagye

 
 
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Assistant

 

Mrs Maureen Francis +44 (0)20 7594 2793

 
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Location

 

GN1Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Pinato:2019:10.1038/s41416-018-0373-6,
author = {Pinato, D and Brown, MW and Trousil, S and Aboagye, E and Beaumont, J and Zhang, H and Coley, HM and Mauri, F and Sharma, R},
doi = {10.1038/s41416-018-0373-6},
journal = {British Journal of Cancer},
pages = {512--521},
title = {Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma.},
url = {http://dx.doi.org/10.1038/s41416-018-0373-6},
volume = {120},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Pinato,D
AU  - Brown,MW
AU  - Trousil,S
AU  - Aboagye,E
AU  - Beaumont,J
AU  - Zhang,H
AU  - Coley,HM
AU  - Mauri,F
AU  - Sharma,R
DO  - 10.1038/s41416-018-0373-6
EP  - 521
PY  - 2019///
SN  - 0007-0920
SP  - 512
TI  - Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma.
T2  - British Journal of Cancer
UR  - http://dx.doi.org/10.1038/s41416-018-0373-6
UR  - http://hdl.handle.net/10044/1/66537
VL  - 120
ER  -
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