Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: Role of endothelin-A receptor-activated ABCB1 expression
  • Metaadatok
Tartalom: http://real.mtak.hu/46237/
Archívum: MTA Könyvtár
Gyűjtemény: Status = Published

Type = Article
Cím:
Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: Role of endothelin-A receptor-activated ABCB1 expression
Létrehozó:
Englinger, B.
Lötsch, D.
Pirker, Christine
Mohr, T.
van Schoonhoven, S.
Szakács, Gergely
Kiadó:
Impact Journals
Dátum:
2016
Téma:
R850-854 Experimental medicine / kisérleti orvostudomány
RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkolĂłgia
Tartalmi leírás:
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 NFÎşB 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.
Nyelv:
angol
Típus:
Article
PeerReviewed
info:eu-repo/semantics/article
Formátum:
text
Azonosító:
Englinger, B. and Lötsch, D. and Pirker, Christine and Mohr, T. and van Schoonhoven, S. and Szakács, Gergely (2016) Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: Role of endothelin-A receptor-activated ABCB1 expression. Oncotarget, 7 (31). pp. 50161-50179. ISSN 1949-2553
Kapcsolat:
MTMT:3172095; doi:10.18632/oncotarget.10324