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.

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…A notable array of compounds have been described in recent years to (partially) inhibit FGFR, next to other Tyrosine Kinase Receptor (TKR), including Vascular Endothelial Growth Factor Receptor (VEGFR), Platelet Derived Growth Factor Receptor (PDGFR), Fms-like tyrosine kinase 3 (FLT-3), c-Kit (c-KIT), Rearranged during transfection (RET) and BCR-ABL. These compounds include Brivatinib (Cai et al, 2008), Lenvatinib (Yamamoto et al, 2014), Regorafenib (Wilhelm et al, 2011), Ponatinib (Gozgit et al, 2012), Dovitininb (Porta et al, 2015), Nintedanib (Dhillon, 2015), Pazopanib (Prince et al, 2009), Orantinib (Ohta et al, 2009), ENMD 2076 (Matulonis et al, 2013), Lucitanib (Bello et al, 2011), PBI 05204 (Hong et al, 2014), Sunitinib (Welti et al, 2011) and Cediranib (Wedge et al, 2005). Although some of them have achieved approval for use against several cancer types, this section only focuses on those multi-target inhibitors that have included a subset of patients with FGFR alterations (Table 1).…”

Durability of Kinase-Directed Therapies—A Network Perspective on Response and Resistance

“…Tumor cell signaling networks and the microenvironment change during disease progression, which influences a drug's effectiveness. An early reliance of a tumor on angiogenesis is supplanted by new capabilities to invoke vasculogenesis or co-opt existing vasculature, circumventing the benefit derived from VEGFR blockade by targeted kinase therapies (53). These findings underscore the importance of understanding the dynamic nature of signaling networks.…”

Targeting fibroblast growth factor receptor (FGFR) pathway in renal cell carcinoma

“…On the other hand, the small molecule TKI PD173074, a potent reversible inhibitor of FGFR tyrosine kinase activity, [29] seems to inhibit FGF2-mediated resistance to sunitinib in preclinical models. [16] Conclusion A multidisciplinary integrated approach is needed for deeper understanding of tumor biology of RCC. An increasing number of molecules are emerging in the treatment landscape of this tumor.…”

“…Moreover, FGF serum levels significantly increase in mRCC patients with disease progression while receiving sunitinib therapy, supporting the potential FGF-pathway role as a potent mediator of endothelial cell resistance to VEGFR inhibitors. [15,16] …”