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Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma

Background: FGFR inhibition has been proposed as treatment for dedifferentiated liposarcoma (DDLPS) with amplified FRS2, but we previously only demonstrated transient cytostatic effects when treating FRS2-amplified DDLPS cells with NVP-BGJ398. Methods: Effects of the more potent FGFR inhibitor LY287...

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Autores principales: Hanes, Robert, Munthe, Else, Grad, Iwona, Han, Jianhua, Karlsen, Ida, McCormack, Emmet, Meza-Zepeda, Leonardo A., Stratford, Eva Wessel, Myklebost, Ola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406403/
https://www.ncbi.nlm.nih.gov/pubmed/30795553
http://dx.doi.org/10.3390/cells8020189
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author Hanes, Robert
Munthe, Else
Grad, Iwona
Han, Jianhua
Karlsen, Ida
McCormack, Emmet
Meza-Zepeda, Leonardo A.
Stratford, Eva Wessel
Myklebost, Ola
author_facet Hanes, Robert
Munthe, Else
Grad, Iwona
Han, Jianhua
Karlsen, Ida
McCormack, Emmet
Meza-Zepeda, Leonardo A.
Stratford, Eva Wessel
Myklebost, Ola
author_sort Hanes, Robert
collection PubMed
description Background: FGFR inhibition has been proposed as treatment for dedifferentiated liposarcoma (DDLPS) with amplified FRS2, but we previously only demonstrated transient cytostatic effects when treating FRS2-amplified DDLPS cells with NVP-BGJ398. Methods: Effects of the more potent FGFR inhibitor LY2874455 were investigated in three DDLPS cell lines by measuring effects on cell growth and apoptosis in vitro and also testing efficacy in vivo. Genome, transcriptome and protein analyses were performed to characterize the signaling components in the FGFR pathway. Results: LY2874455 induced a stronger, longer-lasting growth inhibitory effect and moderate level of apoptosis for two cell lines. The third cell line, did not respond to FGFR inhibition, suggesting that FRS2 amplification alone is not sufficient to predict response. Importantly, efficacy of LY2874455 was confirmed in vivo, using an independent FRS2-amplified DDLPS xenograft model. Expression of FRS2 was similar in the responding and non-responding cell lines and we could not find any major difference in downstream FGFR signaling. The only FGF expressed by unstimulated non-responding cells was the intracellular ligand FGF11, whereas the responding cell lines expressed extracellular ligand FGF2. Conclusion: Our study supports LY2874455 as a better therapy than NVP-BGJ398 for FRS2-amplified liposarcoma, and a clinical trial is warranted.
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spelling pubmed-64064032019-03-19 Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma Hanes, Robert Munthe, Else Grad, Iwona Han, Jianhua Karlsen, Ida McCormack, Emmet Meza-Zepeda, Leonardo A. Stratford, Eva Wessel Myklebost, Ola Cells Article Background: FGFR inhibition has been proposed as treatment for dedifferentiated liposarcoma (DDLPS) with amplified FRS2, but we previously only demonstrated transient cytostatic effects when treating FRS2-amplified DDLPS cells with NVP-BGJ398. Methods: Effects of the more potent FGFR inhibitor LY2874455 were investigated in three DDLPS cell lines by measuring effects on cell growth and apoptosis in vitro and also testing efficacy in vivo. Genome, transcriptome and protein analyses were performed to characterize the signaling components in the FGFR pathway. Results: LY2874455 induced a stronger, longer-lasting growth inhibitory effect and moderate level of apoptosis for two cell lines. The third cell line, did not respond to FGFR inhibition, suggesting that FRS2 amplification alone is not sufficient to predict response. Importantly, efficacy of LY2874455 was confirmed in vivo, using an independent FRS2-amplified DDLPS xenograft model. Expression of FRS2 was similar in the responding and non-responding cell lines and we could not find any major difference in downstream FGFR signaling. The only FGF expressed by unstimulated non-responding cells was the intracellular ligand FGF11, whereas the responding cell lines expressed extracellular ligand FGF2. Conclusion: Our study supports LY2874455 as a better therapy than NVP-BGJ398 for FRS2-amplified liposarcoma, and a clinical trial is warranted. MDPI 2019-02-21 /pmc/articles/PMC6406403/ /pubmed/30795553 http://dx.doi.org/10.3390/cells8020189 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hanes, Robert
Munthe, Else
Grad, Iwona
Han, Jianhua
Karlsen, Ida
McCormack, Emmet
Meza-Zepeda, Leonardo A.
Stratford, Eva Wessel
Myklebost, Ola
Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma
title Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma
title_full Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma
title_fullStr Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma
title_full_unstemmed Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma
title_short Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma
title_sort preclinical evaluation of the pan-fgfr inhibitor ly2874455 in frs2-amplified liposarcoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406403/
https://www.ncbi.nlm.nih.gov/pubmed/30795553
http://dx.doi.org/10.3390/cells8020189
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