Welti, J. C., Gourlaouen, M., Powles, T., Kudahetti, S. C., Wilson, P., Berney, D. M., Reynolds, A. R. (2011) Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib. ONCOGENE, 30 (10). pp. 1183-1193. ISSN 0950-9232

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Abstract

The vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor sunitinib has been approved for first-line treatment of patients with metastatic renal cancer and is currently being trialled in other cancers. However, the effectiveness of this anti-angiogenic agent is limited by the presence of innate and acquired drug resistance. By screening a panel of candidate growth factors we identified fibroblast growth factor 2 (FGF2) as a potent regulator of endothelial cell sensitivity to sunitinib. We show that FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib and that FGF2 can suppress sunitinib-induced retraction of tubules. Importantly, these effects of FGF2 were ablated by PD173074, a small molecule inhibitor of FGF receptor signalling. We also show that FGF2 can stimulate pro-angiogenic signalling pathways in endothelial cells despite the presence of sunitinib. Finally, analysis of clinical renal-cancer samples demonstrates that a large proportion of renal cancers strongly express FGF2. We suggest that therapeutic strategies designed to simultaneously target both VEGF and FGF2 signalling may prove more efficacious than sunitinib in renal cancer patients whose tumours express FGF2. Oncogene (2011) 30, 1183-1193; doi:10.1038/onc.2010.503; published online 8 November 2010

Item Type:	Article
Authors (ICR Faculty only):	Reynolds, Andrew
All Authors:	Welti, J. C., Gourlaouen, M., Powles, T., Kudahetti, S. C., Wilson, P., Berney, D. M., Reynolds, A. R.
Additional Information:	ISI Document Delivery No.: 732QD Times Cited: 0 Cited Reference Count: 51 Welti, J. C. Gourlaouen, M. Powles, T. Kudahetti, S. C. Wilson, P. Berney, D. M. Reynolds, A. R. Breakthrough Breast Cancer ; Pfizer Global Pharmaceuticals Thomas Powles is the recipient of an educational research grant from Pfizer Global Pharmaceuticals. The other authors declare no potential conflict of interest. We would like to thank Alan Ashworth, Clare Isacke and Nicholas Turner for critical comments on the paper and Breakthrough Breast Cancer for research funding. Nature publishing group London
Uncontrolled Keywords:	angiogenesis growth factors sunitinib renal cancer resistance tyrosine kinase inhibitor in-vitro antitumor-activity tumor angiogenesis targeted therapy interferon-alpha lung-cancer carcinoma vegf resistance
Research teams:	Closed research groups > Tumour Biology
Depositing User:	Barry Jenkins
Date Deposited:	05 Apr 2011 11:37
Last Modified:	25 Apr 2017 14:36
URI:	http://publications.icr.ac.uk/id/eprint/10618

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