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

被引：20

作者：

Englinger, Bernhard ^{[1
]}

Loetsch, Daniela ^{[1
]}

Pirker, Christine ^{[1
]}

Mohr, Thomas ^{[1
]}

van Schoonhoven, Sushilla ^{[1
]}

Boidol, Bernd ^{[2
]}

Lardeau, Charles-Hugues ^{[2
]}

Spitzwieser, Melanie ^{[3
]}

Szabo, Pal ^{[4
]}

Heffeter, Petra ^{[1
]}

Lang, Irene ^{[5
]}

Cichna-Markl, Margit ^{[3
]}

Grasl-Kraupp, Bettina ^{[1
]}

Marian, Brigitte ^{[1
]}

Grusch, Michael ^{[1
]}

Kubicek, Stefan ^{[2
]}

Szakacs, Gergely ^{[1
,6
]}

Berger, Walter ^{[1
]}

机构：

[1] Med Univ Vienna, Dept Med 1, Inst Canc Res, Vienna, Austria

[2] Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria

[3] Univ Vienna, Dept Analyt Chem, Vienna, Austria

[4] Hungarian Acad Sci, Res Ctr Nat Sci, Inst Organ Chem, Budapest, Hungary

[5] Med Univ Vienna, Dept Med 2, Div Cardiol, Vienna, Austria

[6] Hungarian Acad Sci, Res Ctr Nat Sci, Inst Enzymol, Budapest, Hungary

来源：

ONCOTARGET | 2016年 / 7卷 / 31期

基金：

奥地利科学基金会;

关键词：

small cell lung cancer; FGFR1; nintedanib; ABCB1; endothelin-A receptor; TYROSINE KINASE INHIBITORS; GROWTH-FACTOR-RECEPTOR; MULTIDRUG-RESISTANCE; FGFR1; AMPLIFICATION; P-GLYCOPROTEIN; THERAPEUTIC TARGETS; TRANSPORTERS; CARCINOMA; PROTEIN; CHEMORESISTANCE;

D O I：

10.18632/oncotarget.10324

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 NF kappa B 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.

引用

页码：50161 / 50179

页数：19