Imperial College London
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Dr Olivier E. Pardo

Faculty of Medicine, Department of Surgery & Cancer

Reader in Cancer Cell Signalling
 
 
 
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Contact

 

+44 (0)20 7594 2814o.pardo Website CV

 
 
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Location

 

145ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Pardo:2018:10.18632/oncotarget.25213,
author = {Pardo, OE and Rupniewska, E and Roy, R and Mauri, FA and Liu, X and Kaliszczak, M and Tommasi, AM and Aboagye, E and Seckl, MJ},
doi = {10.18632/oncotarget.25213},
journal = {Oncotarget},
pages = {27346--27362},
title = {Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors},
url = {http://dx.doi.org/10.18632/oncotarget.25213},
volume = {9},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Lung cancer is the main cancer killer in both men and women, mostly due to the rapid development of drug resistant metastatic disease. Here, we evaluate the potential involvement of SRC family kinases (SFK) in lung cancer biology and assess the possible benefits of their inhibition as a therapeutic approach. We demonstrated that various SRC family members, including LYN and LCK, normally expressed solely in hematopoietic cells and neural tissues, are overexpressed and activated in a panel of SCLC and NSCLC cell lines. This was clinically relevant as LYN and FYN are also overexpressed in lung cancer clinical specimens. Moreover, LYN overexpression correlated with decreased patient survival on univariate and multivariate analysis. Dasatinib (BMS-354825), a SRC/ABL inhibitor, effectively blocked SFK activation at nanomolar concentrations which correlated with a significant decrease in cell numbers of multiple lung cancer cell lines. This effect was matched by a decrease in DNA synthesis, but only moderate induction of apoptosis. Indeed, dasatinib as well as PP2, another SFK inhibitor, strongly induced autophagy that likely prevented apoptosis. However, inhibition of this autophagic response induced robust apoptosis and sensitised lung cancer cells to dasatinib in vitro and in vivo. Our results provide an explanation for why dasatinib failed in NSCLC clinical trials. Furthermore, our data suggest that combining SFK inhibitors with autophagy inhibitors could provide a novel therapeutic approach in this disease.
AU  - Pardo,OE
AU  - Rupniewska,E
AU  - Roy,R
AU  - Mauri,FA
AU  - Liu,X
AU  - Kaliszczak,M
AU  - Tommasi,AM
AU  - Aboagye,E
AU  - Seckl,MJ
DO  - 10.18632/oncotarget.25213
EP  - 27362
PY  - 2018///
SN  - 1949-2553
SP  - 27346
TI  - Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors
T2  - Oncotarget
UR  - http://dx.doi.org/10.18632/oncotarget.25213
UR  - http://hdl.handle.net/10044/1/58904
VL  - 9
ER  -
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