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

2016; Impact Journals LLC; Volume: 7; Issue: 31 Linguagem: Inglês

10.18632/oncotarget.10324

1949-2553

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

Lung Cancer Research Studies

// Bernhard Englinger 1 , Daniela Lötsch 1 , Christine Pirker 1 , Thomas Mohr 1 , Sushilla van Schoonhoven 1 , Bernd Boidol 2 , Charles-Hugues Lardeau 2 , Melanie Spitzwieser 3 , Pál Szabó 4 , Petra Heffeter 1 , Irene Lang 5 , Margit Cichna-Markl 3 , Bettina Grasl-Kraupp 1 , Brigitte Marian 1 , Michael Grusch 1 , Stefan Kubicek 2 , Gergely Szakács 1, 6 , Walter Berger 1 1 Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria 2 CeMM Research Center for Molecular Medicine of The Austrian Academy of Sciences, Vienna, Austria 3 Department of Analytical Chemistry, University of Vienna, Vienna, Austria 4 Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary 5 Division of Cardiology, Department of Medicine II, Medical University of Vienna, Vienna, Austria 6 Institute 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 (ET A R) signaling axis. Indeed, ET A R inhibition resensitized DMS114/NIN cells against nintedanib by downregulation of ABCB1 expression. PKC and downstream NFκB were identified as major downstream players in ET A R-mediated ABCB1 hyperactivation. Summarizing, ABCB1 needs to be considered as a factor underlying nintedanib resistance. Combination approaches with ET A R antagonists or switching to non-ABCB1 substrate FGFR inhibitors represent innovative strategies to manage nintedanib resistance in lung cancer.