title: Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: role of endothelin-A receptor-activated ABCB1 expression.
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.
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Englinger
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Lötsch
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Pirker
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mohr
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Sushilla
authors.initials: S
authors.lastname: van Schoonhoven
authors.affiliation: CeMM Research Center for Molecular Medicine of The Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Bernd
authors.initials: B
authors.lastname: Boidol
authors.affiliation: CeMM Research Center for Molecular Medicine of The Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Charles-Hugues
authors.initials: CH
authors.lastname: Lardeau
authors.affiliation: Department of Analytical Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Melanie
authors.initials: M
authors.lastname: Spitzwieser
authors.affiliation: Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Pál
authors.initials: P
authors.lastname: Szabó
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.affiliation: Division of Cardiology, Department of Medicine II, Medical University of Vienna, Vienna, Austria.
authors.forename: Irene
authors.initials: I
authors.lastname: Lang
authors.affiliation: Department of Analytical Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Margit
authors.initials: M
authors.lastname: Cichna-Markl
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Marian
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.affiliation: CeMM Research Center for Molecular Medicine of The Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicek
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.|Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Gergely
authors.initials: G
authors.lastname: Szakács
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy*; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002469:Cell Separation; D002470:Cell Survival; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy*; D009364:Neoplasm Recurrence, Local; D010641:Phenotype; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D017466:Receptors, Endothelin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D007211:Indoles; D017466:Receptors, Endothelin; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; C530716:nintedanib
keywords: ABCB1; FGFR1; endothelin-A receptor; nintedanib; small cell lung cancer