Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

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. Access through your institution Buy or

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like to thank Alan Ashworth, Clare Isacke and Nicholas Turner for critical comments on the paper and Breakthrough Breast Cancer for research funding. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Tumour Angiogenesis Group, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK J C Welti, M Gourlaouen & A R Reynolds * Centre for

Molecular Oncology, Queen Mary University of London, Barts & The London School Of Medicine & Dentistry, Institute of Cancer, John Vane Science Centre, Charterhouse Square, London,

UK T Powles, S C Kudahetti & D M Berney * Department of Medical Oncology, West Smithfield, London, UK, P Wilson Authors * J C Welti View author publications You can also search for this

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can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to A R Reynolds. ETHICS DECLARATIONS COMPETING INTERESTS Thomas Powles is the recipient of an

educational research grant from Pfizer Global Pharmaceuticals. The other authors declare no potential conflict of interest. ADDITIONAL INFORMATION Supplementary Information accompanies the

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Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Welti, J., Gourlaouen, M., Powles, T. _et al._ Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib.

_Oncogene_ 30, 1183–1193 (2011). https://doi.org/10.1038/onc.2010.503 Download citation * Received: 21 June 2010 * Revised: 05 August 2010 * Accepted: 03 September 2010 * Published: 08

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angiogenesis * growth factors * sunitinib * renal cancer * resistance