Englinger Bernhard, Lötsch Daniela, Pirker Christine, Mohr Thomas, van Schoonhoven Sushilla, Boidol Bernd, Lardeau Charles-Hugues, Spitzwieser Melanie, Szabó Pál, Heffeter Petra, Lang Irene, Cichna-Markl Margit, Grasl-Kraupp Bettina, Marian Brigitte, Grusch Michael, Kubicek Stefan, Szakács Gergely, Berger Walter
Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria.
CeMM Research Center for Molecular Medicine of The Austrian Academy of Sciences, Vienna, Austria.
Oncotarget. 2016 Aug 2;7(31):50161-50179. doi: 10.18632/oncotarget.10324.
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.
基因组扩增的成纤维细胞生长因子受体1（FGFR1）是特定肺癌亚组中的致癌驱动因素，并可预测该患者队列对FGFR1抑制剂的敏感性。FGFR抑制剂尼达尼布最近已被批准用于治疗肺腺癌，目前正在对小细胞肺癌（SCLC）进行评估。然而，由于尼达尼布耐药性的发展可能会出现肿瘤复发。因此，我们旨在阐明FGFR1驱动的肺癌中获得性尼达尼布耐药的分子机制。对FGFR1驱动的SCLC细胞系DMS114（DMS114/NIN）进行慢性尼达尼布暴露，但对两个NSCLC细胞系未进行慢性暴露，结果诱导了多药耐药转运蛋白ABCB1的大量过表达。事实上，我们证明尼达尼布既是ABCB1介导的外排的底物，也是其调节剂。重要的是，致癌性FGFR1信号轴在DMS114/NIN细胞中仍然活跃，而生物信息学分析表明内皮素-A受体（ETAR）信号轴过度激活。事实上，ETAR抑制通过下调ABCB1表达使DMS114/NIN细胞对尼达尼布重新敏感。PKC和下游NFκB被确定为ETAR介导的ABCB1过度激活的主要下游参与者。总之，ABCB1需要被视为尼达尼布耐药的一个因素。与ETAR拮抗剂联合使用或改用非ABCB1底物的FGFR抑制剂是应对肺癌中尼达尼布耐药的创新策略。
