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Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors

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Title: Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors
Authors: Pardo, OE
Rupniewska, E
Roy, R
Mauri, FA
Liu, X
Kaliszczak, M
Tommasi, AM
Aboagye, E
Seckl, MJ
Item Type: Journal Article
Abstract: 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.
Issue Date: 8-Jun-2018
Date of Acceptance: 4-Apr-2018
URI: http://hdl.handle.net/10044/1/58904
DOI: https://dx.doi.org/10.18632/oncotarget.25213
ISSN: 1949-2553
Publisher: Impact Journals
Start Page: 27346
End Page: 27362
Journal / Book Title: Oncotarget
Volume: 9
Copyright Statement: © 2018 Rupniewska et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor/Funder: Cancer Research UK
Funder's Grant Number: C1312/A6119
Keywords: SRC
apoptosis
dasatinib
lung cancer
resistance
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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