Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC

Kristine Raaby Gammelgaard; Johan Vad-Nielsen; Michelle Simone Clement; Simone Weiss; Tina Fuglsang Daugaard; Frederik Dagnæs-Hansen; Peter Meldgaard; Boe Sandahl Sorensen; Anders Lade Nielsen

doi:10.1016/j.tranon.2018.11.017

Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC

Transl Oncol. 2019 Mar;12(3):432-440. doi: 10.1016/j.tranon.2018.11.017. Epub 2018 Dec 16.

Authors

Kristine Raaby Gammelgaard¹, Johan Vad-Nielsen², Michelle Simone Clement³, Simone Weiss², Tina Fuglsang Daugaard², Frederik Dagnæs-Hansen², Peter Meldgaard⁴, Boe Sandahl Sorensen³, Anders Lade Nielsen⁵

Affiliations

¹ Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
² Department of Biomedicine, Aarhus University, Aarhus, Denmark.
³ Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
⁴ Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
⁵ Department of Biomedicine, Aarhus University, Aarhus, Denmark. Electronic address: aln@biomed.au.dk.

Abstract

Non-small cell lung carcinoma patients with epidermal growth factor receptor (EGFR) mutations are offered EGFR tyrosine kinase inhibitors (TKI) as first line treatment, but 20-40% of these patients do not respond. High expression of alternative receptor tyrosine kinases, such as Fibroblast growth factor receptor 1 (FGFR1), potentially mediates intrinsic EGFR TKI resistance. To study this in molecular detail, we used CRISPR-dCas9 Synergistic Activation Mediator (SAM) for up-regulation of FGFR1 in physiological relevant levels in the EGFR mutated NSCLC cell lines HCC827 and PC9 thereby generating HCC827^gFGFR1 and PC9^gFGFR1. The sensitivity to the TKI erlotinib was investigated in vitro and in a BALBc nu/nu mouse xenograft model. FGFR1 up-regulation decreased TKI-sensitivity in both NSCLC cell lines in the presence of the ligand fibroblast growth factor 2 (FGF2). Xenografts were established with PC9^gFGFR1 cells and it was demonstrated that there was no significant difference in tumor size between TKI- and vehicle-treated PC9^gFGFR1 tumors. This supports decreased TKI-sensitivity in NSCLC cells with FGFR1 up-regulation. Our study points to FGFR1 signaling being an intrinsic resistance mechanism abolishing TKI response in EGFR mutated NSCLC.