Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors

Ewa Rupniewska, Rajat Roy, Francesco A. Mauri, Xinxue Liu, Maciej Kaliszczak, Guido Bellezza, Lucio Cagini, Mattia Barbareschi, Stefano Ferrero, Anna M. Tommasi, Eric Aboagye, Michael J. Seckl, Olivier E. Pardo

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)27346-27362
Number of pages17
JournalOncotarget
Volume9
Issue number44
DOIs
Publication statusPublished - Jun 1 2018

Fingerprint

src-Family Kinases
Autophagy
Lung Neoplasms
Phosphotransferases
Apoptosis
Cell Line
Multivariate Analysis
Cell Count
Dasatinib
Clinical Trials
Survival
DNA
Therapeutics
Pharmaceutical Preparations
Neoplasms

Keywords

  • Apoptosis
  • Dasatinib
  • Lung cancer
  • Resistance
  • SRC

ASJC Scopus subject areas

  • Oncology

Cite this

Rupniewska, E., Roy, R., Mauri, F. A., Liu, X., Kaliszczak, M., Bellezza, G., ... Pardo, O. E. (2018). Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors. Oncotarget, 9(44), 27346-27362. https://doi.org/10.18632/oncotarget.25213

Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors. / Rupniewska, Ewa; Roy, Rajat; Mauri, Francesco A.; Liu, Xinxue; Kaliszczak, Maciej; Bellezza, Guido; Cagini, Lucio; Barbareschi, Mattia; Ferrero, Stefano; Tommasi, Anna M.; Aboagye, Eric; Seckl, Michael J.; Pardo, Olivier E.

In: Oncotarget, Vol. 9, No. 44, 01.06.2018, p. 27346-27362.

Research output: Contribution to journalArticle

Rupniewska, E, Roy, R, Mauri, FA, Liu, X, Kaliszczak, M, Bellezza, G, Cagini, L, Barbareschi, M, Ferrero, S, Tommasi, AM, Aboagye, E, Seckl, MJ & Pardo, OE 2018, 'Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors', Oncotarget, vol. 9, no. 44, pp. 27346-27362. https://doi.org/10.18632/oncotarget.25213
Rupniewska E, Roy R, Mauri FA, Liu X, Kaliszczak M, Bellezza G et al. Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors. Oncotarget. 2018 Jun 1;9(44):27346-27362. https://doi.org/10.18632/oncotarget.25213
Rupniewska, Ewa ; Roy, Rajat ; Mauri, Francesco A. ; Liu, Xinxue ; Kaliszczak, Maciej ; Bellezza, Guido ; Cagini, Lucio ; Barbareschi, Mattia ; Ferrero, Stefano ; Tommasi, Anna M. ; Aboagye, Eric ; Seckl, Michael J. ; Pardo, Olivier E. / Targeting autophagy sensitises lung cancer cells to Src family kinase inhibitors. In: Oncotarget. 2018 ; Vol. 9, No. 44. pp. 27346-27362.
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