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

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 fa...

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Autores principales: Gammelgaard, Kristine Raaby, Vad-Nielsen, Johan, Clement, Michelle Simone, Weiss, Simone, Daugaard, Tina Fuglsang, Dagnæs-Hansen, Frederik, Meldgaard, Peter, Sorensen, Boe Sandahl, Nielsen, Anders Lade
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297127/
https://www.ncbi.nlm.nih.gov/pubmed/30562682
http://dx.doi.org/10.1016/j.tranon.2018.11.017
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author Gammelgaard, Kristine Raaby
Vad-Nielsen, Johan
Clement, Michelle Simone
Weiss, Simone
Daugaard, Tina Fuglsang
Dagnæs-Hansen, Frederik
Meldgaard, Peter
Sorensen, Boe Sandahl
Nielsen, Anders Lade
author_facet Gammelgaard, Kristine Raaby
Vad-Nielsen, Johan
Clement, Michelle Simone
Weiss, Simone
Daugaard, Tina Fuglsang
Dagnæs-Hansen, Frederik
Meldgaard, Peter
Sorensen, Boe Sandahl
Nielsen, Anders Lade
author_sort Gammelgaard, Kristine Raaby
collection PubMed
description 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.
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spelling pubmed-62971272018-12-19 Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC Gammelgaard, Kristine Raaby Vad-Nielsen, Johan Clement, Michelle Simone Weiss, Simone Daugaard, Tina Fuglsang Dagnæs-Hansen, Frederik Meldgaard, Peter Sorensen, Boe Sandahl Nielsen, Anders Lade Transl Oncol Original article 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. Neoplasia Press 2018-12-16 /pmc/articles/PMC6297127/ /pubmed/30562682 http://dx.doi.org/10.1016/j.tranon.2018.11.017 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original article
Gammelgaard, Kristine Raaby
Vad-Nielsen, Johan
Clement, Michelle Simone
Weiss, Simone
Daugaard, Tina Fuglsang
Dagnæs-Hansen, Frederik
Meldgaard, Peter
Sorensen, Boe Sandahl
Nielsen, Anders Lade
Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC
title Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC
title_full Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC
title_fullStr Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC
title_full_unstemmed Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC
title_short Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC
title_sort up-regulated fgfr1 expression as a mediator of intrinsic tki resistance in egfr-mutated nsclc
topic Original article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297127/
https://www.ncbi.nlm.nih.gov/pubmed/30562682
http://dx.doi.org/10.1016/j.tranon.2018.11.017
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