Oncotarget

Research Papers:

Characterization of FGFR signaling in prostate cancer stem cells and inhibition via TKI treatment

Juyeon Ko, April N. Meyer, Martin Haas and Daniel J. Donoghue _

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Oncotarget. 2021; 12:22-36. https://doi.org/10.18632/oncotarget.27859

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Abstract

Juyeon Ko1, April N. Meyer1, Martin Haas2 and Daniel J. Donoghue1,2

1 Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA

2 Moores UCSD Cancer Center, University of California San Diego, La Jolla, CA, USA

Correspondence to:

Daniel J. Donoghue,email: ddonoghue@ucsd.edu

Keywords: metastatic castrate-resistant prostate cancer; spheroid culture; tyrosine kinase inhibitor

Received: December 15, 2020     Accepted: December 16, 2020     Published: January 05, 2021

Copyright: © 2021 Ko et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

Metastatic castrate-resistant prostate cancer (CRPC) remains uncurable and novel therapies are needed to better treat patients. Aberrant Fibroblast Growth Factor Receptor (FGFR) signaling has been implicated in advanced prostate cancer (PCa), and FGFR1 is suggested to be a promising therapeutic target along with current androgen deprivation therapy. We established a novel in vitro 3D culture system to study endogenous FGFR signaling in a rare subpopulation of prostate cancer stem cells (CSCs) in the cell lines PC3, DU145, LNCaP, and the induced pluripotent iPS87 cell line. 3D-propagation of PCa cells generated spheroids with increased stemness markers ALDH7A1 and OCT4, while inhibition of FGFR signaling by BGJ398 or Dovitinib decreased cell survival and proliferation of 3D spheroids. The 3D spheroids exhibited altered expression of EMT markers associated with metastasis such as E-cadherin, vimentin and Snail, compared to 2D monolayer cells. TKI treatment did not result in significant changes of EMT markers, however, specific inhibition of FGFR signaling by BGJ398 showed more favorable molecular-level changes than treatment with the multi-RTK inhibitor Dovitinib. This study provides evidence for the first time that FGFR1 plays an essential role in the proliferation of PCa CSCs at a molecular and cellular level, and suggests that TKI targeting of FGFR signaling may be a promising strategy for AR-independent CRPC.


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