Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC
| Autor: | Peter Meldgaard, Johan Vad-Nielsen, Simone Weiss, Anders Lade Nielsen, Kristine Raaby Gammelgaard, Tina Fuglsang Daugaard, Michelle Simone Clement, Frederik Dagnæs-Hansen, Boe Sandahl Sorensen |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MECHANISM Cancer Research Original article CELL LUNG-CANCER Cell ERLOTINIB Fibroblast growth factor lcsh:RC254-282 Receptor tyrosine kinase GEFITINIB ACTIVATION 03 medical and health sciences 0302 clinical medicine Gefitinib Downregulation and upregulation medicine Epidermal growth factor receptor biology Chemistry MUTATIONS Fibroblast growth factor receptor 1 lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens respiratory tract diseases 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Erlotinib INHIBITORS medicine.drug ACQUIRED-RESISTANCE |
| Zdroj: | Translational Oncology, Vol 12, Iss 3, Pp 432-440 (2019) Gammelgaard, K R, Vad-Nielsen, J, Clement, M S, Weiss, S, Daugaard, T F, Dagnæs-Hansen, F, Meldgaard, P, Sorensen, B S & Nielsen, A L 2019, ' Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC ', Translational Oncology, vol. 12, no. 3, pp. 432-440 . https://doi.org/10.1016/j.tranon.2018.11.017 Translational Oncology |
| ISSN: | 1936-5233 |
| DOI: | 10.1016/j.tranon.2018.11.017 |
| Popis: | 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 HCC827gFGFR1 and PC9gFGFR1. 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 PC9gFGFR1 cells and it was demonstrated that there was no significant difference in tumor size between TKI- and vehicle-treated PC9gFGFR1 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. |
| Databáze: | OpenAIRE |
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