Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells

Abstract EGFR tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) patients is inevitable. Identification of resistance mechanisms and corresponding targeting strategies can lead to more successful later-line treatment in many patients. Using spectrometry-based proteomics...

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Autores principales:	Mikkel G. Terp, Kirstine Jacobsen, Miguel Angel Molina, Niki Karachaliou, Hans C. Beck, Jordi Bertran-Alamillo, Ana Giménez-Capitán, Andrés F. Cardona, Rafael Rosell, Henrik J. Ditzel
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/4079b23b742f40d7b05c71931a377a85
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spelling	oai:doaj.org-article:4079b23b742f40d7b05c71931a377a852021-12-02T16:14:15ZCombined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells10.1038/s41698-021-00208-w2397-768Xhttps://doaj.org/article/4079b23b742f40d7b05c71931a377a852021-07-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00208-whttps://doaj.org/toc/2397-768XAbstract EGFR tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) patients is inevitable. Identification of resistance mechanisms and corresponding targeting strategies can lead to more successful later-line treatment in many patients. Using spectrometry-based proteomics, we identified increased fibroblast growth factor receptor 1 (FGFR1) expression and Akt activation across erlotinib, gefitinib, and osimertinib EGFR-TKI-resistant cell line models. We show that while combined EGFR-TKI and FGFR inhibition showed some efficacy, simultaneous inhibition of FGFR and Akt or PI3K induced superior synergistic growth inhibition of FGFR1-overexpressing EGFR-TKI-resistant NSCLC cells. This effect was confirmed in vivo. Only dual FGFR and Akt inhibition completely blocked the resistance-mediating signaling pathways downstream of Akt. Further, increased FGFR1 expression was associated with significantly lower PFS in EGFR-TKI-treated NSCLC patients, and increased FGFR1 were demonstrated in a few post- vs. pre-EGFR-TKI treatment clinical biopsies. The superior therapeutic benefit of combining FGFR and Akt inhibitors provide the rationale for clinical trials of this strategy.Mikkel G. TerpKirstine JacobsenMiguel Angel MolinaNiki KarachaliouHans C. BeckJordi Bertran-AlamilloAna Giménez-CapitánAndrés F. CardonaRafael RosellHenrik J. DitzelNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Mikkel G. Terp Kirstine Jacobsen Miguel Angel Molina Niki Karachaliou Hans C. Beck Jordi Bertran-Alamillo Ana Giménez-Capitán Andrés F. Cardona Rafael Rosell Henrik J. Ditzel Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells
description	Abstract EGFR tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) patients is inevitable. Identification of resistance mechanisms and corresponding targeting strategies can lead to more successful later-line treatment in many patients. Using spectrometry-based proteomics, we identified increased fibroblast growth factor receptor 1 (FGFR1) expression and Akt activation across erlotinib, gefitinib, and osimertinib EGFR-TKI-resistant cell line models. We show that while combined EGFR-TKI and FGFR inhibition showed some efficacy, simultaneous inhibition of FGFR and Akt or PI3K induced superior synergistic growth inhibition of FGFR1-overexpressing EGFR-TKI-resistant NSCLC cells. This effect was confirmed in vivo. Only dual FGFR and Akt inhibition completely blocked the resistance-mediating signaling pathways downstream of Akt. Further, increased FGFR1 expression was associated with significantly lower PFS in EGFR-TKI-treated NSCLC patients, and increased FGFR1 were demonstrated in a few post- vs. pre-EGFR-TKI treatment clinical biopsies. The superior therapeutic benefit of combining FGFR and Akt inhibitors provide the rationale for clinical trials of this strategy.
format	article
author	Mikkel G. Terp Kirstine Jacobsen Miguel Angel Molina Niki Karachaliou Hans C. Beck Jordi Bertran-Alamillo Ana Giménez-Capitán Andrés F. Cardona Rafael Rosell Henrik J. Ditzel
author_facet	Mikkel G. Terp Kirstine Jacobsen Miguel Angel Molina Niki Karachaliou Hans C. Beck Jordi Bertran-Alamillo Ana Giménez-Capitán Andrés F. Cardona Rafael Rosell Henrik J. Ditzel
author_sort	Mikkel G. Terp
title	Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells
title_short	Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells
title_full	Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells
title_fullStr	Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells
title_full_unstemmed	Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells
title_sort	combined fgfr and akt pathway inhibition abrogates growth of fgfr1 overexpressing egfr-tki-resistant nsclc cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4079b23b742f40d7b05c71931a377a85
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Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells

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