Next Article in Journal
The MEK-ERK-MST1 Axis Potentiates the Activation of the Extrinsic Apoptotic Pathway during GDC-0941 Treatment in Jurkat T Cells
Next Article in Special Issue
GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells toward Breast Tumor Progression
Previous Article in Journal
Targeting mTOR in Acute Lymphoblastic Leukemia
Previous Article in Special Issue
Fibroblast Growth Factor Receptor 4 Targeting in Cancer: New Insights into Mechanisms and Therapeutic Strategies
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 8
Issue 2
10.3390/cells8020189
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Robert Hanes
1,2,
Else Munthe
1,
Iwona Grad
1,
Jianhua Han
3,
Ida Karlsen
3,4,
Emmet McCormack
3,5,
Leonardo A. Meza-Zepeda
1,2,6,
Eva Wessel Stratford
1 and
Ola Myklebost
1,2,7,*
1
Department of Tumor Biology, Institute of Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway
2
Norwegian Cancer Genomics Consortium, 0379 Oslo, Norway
3
Centre for Cancer Biomarkers (CCBIO), Department of Clinical Sciences, University of Bergen, 5021 Bergen, Norway
4
KinN Therapeutics AS, 5021 Bergen, Norway
5
Department of Internal Medicine, Hematology Section, Haukeland University Hospital, 5021 Bergen, Norway
6
Genomics Core Facility, Department of Core Facilities, Institute of Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, 0379 Oslo, Norway
7
Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
*
Author to whom correspondence should be addressed.
Cells 2019, 8(2), 189; https://doi.org/10.3390/cells8020189
Submission received: 16 January 2019 / Revised: 15 February 2019 / Accepted: 18 February 2019 / Published: 21 February 2019
(This article belongs to the Special Issue Fibroblast Growth Factor Receptor (FGFR) Signaling Pathway in Tumor)
Browse Figures
Versions Notes

Abstract

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.
Keywords: FRS2; FGFR; NVP-BGJ398; LY2874455; sarcoma FRS2; FGFR; NVP-BGJ398; LY2874455; sarcoma
Graphical Abstract

Share and Cite

MDPI and ACS Style

Hanes, R.; Munthe, E.; Grad, I.; Han, J.; Karlsen, I.; McCormack, E.; Meza-Zepeda, L.A.; Stratford, E.W.; Myklebost, O. Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma. Cells 2019, 8, 189. https://doi.org/10.3390/cells8020189

AMA Style

Hanes R, Munthe E, Grad I, Han J, Karlsen I, McCormack E, Meza-Zepeda LA, Stratford EW, Myklebost O. Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma. Cells. 2019; 8(2):189. https://doi.org/10.3390/cells8020189

Chicago/Turabian Style

Hanes, Robert, Else Munthe, Iwona Grad, Jianhua Han, Ida Karlsen, Emmet McCormack, Leonardo A. Meza-Zepeda, Eva Wessel Stratford, and Ola Myklebost. 2019. "Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma" Cells 8, no. 2: 189. https://doi.org/10.3390/cells8020189

APA Style

Hanes, R., Munthe, E., Grad, I., Han, J., Karlsen, I., McCormack, E., Meza-Zepeda, L. A., Stratford, E. W., & Myklebost, O. (2019). Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma. Cells, 8(2), 189. https://doi.org/10.3390/cells8020189

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop