Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib.
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.
Tumour Angiogenesis Group, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
J C
JC
Welti
M
M
Gourlaouen
T
T
Powles
S C
SC
Kudahetti
P
P
Wilson
D M
DM
Berney
A R
AR
Reynolds
D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D042783:Endothelial Cells / Q000187:drug effects*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000077210:Sunitinib; D046888:Tissue Array Analysis
D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D016222:Fibroblast Growth Factor 2; D000077210:Sunitinib