Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors
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Ewa Rupniewska1, Rajat Roy1, Francesco A. Mauri2, Xinxue Liu3, Maciej Kaliszczak1, Guido Bellezza4, Lucio Cagini5, Mattia Barbareschi6, Stefano Ferrero7, Anna M. Tommasi1, Eric Aboagye1, Michael J. Seckl1 and Olivier E. Pardo1
1Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
2Department of Histopathology and Imperial College London, London, United Kingdom
3Statistical Advisory Service, Imperial College London, London, United Kingdom
4Institute of Pathology, Division of Cancer Research, Perugia Medical School, University of Perugia, Perugia, Italy
5Department of Thoracic Surgery, Division of Cancer Research, Perugia Medical School, University of Perugia, Perugia, Italy
6Unit of Surgical Pathology, Laboratory of Molecular Pathology S. Chiara Hospital, Trento, Italy
7Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
Michael J. Seckl, email: [email protected]
Olivier E. Pardo, email: [email protected]
Keywords: lung cancer; SRC; dasatinib; resistance; apoptosis
Received: October 20, 2017 Accepted: April 04, 2018 Published: June 08, 2018
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.
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