Oncotarget

Research Papers:

Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: role of endothelin-A receptor-activated ABCB1 expression

Bernhard Englinger, Daniela Lötsch, Christine Pirker, Thomas Mohr, Sushilla van Schoonhoven, Bernd Boidol, Charles-Hugues Lardeau, Melanie Spitzwieser, Pál Szabó, Petra Heffeter, Irene Lang, Margit Cichna-Markl, Bettina Grasl-Kraupp, Brigitte Marian, Michael Grusch, Stefan Kubicek, Gergely Szakács and Walter Berger _

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Oncotarget. 2016; 7:50161-50179. https://doi.org/10.18632/oncotarget.10324

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Abstract

Bernhard Englinger1, Daniela Lötsch1, Christine Pirker1, Thomas Mohr1, Sushilla van Schoonhoven1, Bernd Boidol2, Charles-Hugues Lardeau2, Melanie Spitzwieser3, Pál Szabó4, Petra Heffeter1, Irene Lang5, Margit Cichna-Markl3, Bettina Grasl-Kraupp1, Brigitte Marian1, Michael Grusch1, Stefan Kubicek2, Gergely Szakács1,6, Walter Berger1

1Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria

2CeMM Research Center for Molecular Medicine of The Austrian Academy of Sciences, Vienna, Austria

3Department of Analytical Chemistry, University of Vienna, Vienna, Austria

4Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary

5Division of Cardiology, Department of Medicine II, Medical University of Vienna, Vienna, Austria

6Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary

Correspondence to:

Walter Berger, email: walter.berger@meduniwien.ac.at

Keywords: small cell lung cancer, FGFR1, nintedanib, ABCB1, endothelin-A receptor

Received: March 08, 2016     Accepted: June 13, 2016     Published: June 29, 2016

ABSTRACT

Genomically amplified fibroblast growth factor receptor 1 (FGFR1) is an oncogenic driver in defined lung cancer subgroups and predicts sensibility against FGFR1 inhibitors in this patient cohort. The FGFR inhibitor nintedanib has recently been approved for treatment of lung adenocarcinoma and is currently evaluated for small cell lung cancer (SCLC). However, tumor recurrence due to development of nintedanib resistance might occur. Hence, we aimed at characterizing the molecular mechanisms underlying acquired nintedanib resistance in FGFR1-driven lung cancer. Chronic nintedanib exposure of the FGFR1-driven SCLC cell line DMS114 (DMS114/NIN) but not of two NSCLC cell lines induced massive overexpression of the multidrug-resistance transporter ABCB1. Indeed, we proved nintedanib to be both substrate and modulator of ABCB1-mediated efflux. Importantly, the oncogenic FGFR1 signaling axis remained active in DMS114/NIN cells while bioinformatic analyses suggested hyperactivation of the endothelin-A receptor (ETAR) signaling axis. Indeed, ETAR inhibition resensitized DMS114/NIN cells against nintedanib by downregulation of ABCB1 expression. PKC and downstream NFκB were identified as major downstream players in ETAR-mediated ABCB1 hyperactivation. Summarizing, ABCB1 needs to be considered as a factor underlying nintedanib resistance. Combination approaches with ETAR antagonists or switching to non-ABCB1 substrate FGFR inhibitors represent innovative strategies to manage nintedanib resistance in lung cancer.


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PII: 10324