Activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinases (RTKs) vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR), controls the initiation of tumor neoangiogenesis.1 Of these, VEGF was the first vascular-specific growth factor to be characterized and is one of the most critical drivers of tumor angiogenesis.2 Of the three closely related members of the VEGFR family, the major effects of VEGF on vessel growth and permeability are mediated via VEGFR2.3, 4 A range of multitargeted kinase inhibitors has been developed, with a focus on targeting VEGFR2 to treat cancer. They include sorafenib, which has been approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma5 and sunitinib, which has been approved for the treatment of RCC and imatinib-resistant gastrointestinal stromal tumor (GIST).6 Furthermore, the VEGF-intercepting antibody bevacizumab has been shown to be clinically effective in antiangiogenic tumor therapy.7

Many other growth factors and receptors, in addition to VEGF and its receptors, have been shown to work in a complementary and coordinated manner with established pathways to regulate tumor growth and angiogenesis, suggesting that blockade of multiple growth factors and receptor pathways may be needed to increase the efficacy of cancer therapy.8 These pathways include FGFR, which is activated by a range of functionally defined ligands, leading to tumor cell proliferation and differentiation via several downstream signaling pathways9 and PDGFR, which supports vessel stabilization by modulating the recruitment and maturation of pericytes.10

Tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) is a crucial regulator of angiogenesis11 that is exclusively or predominantly expressed on endothelial cells and is indispensible for the maturation of immature vessels, via interactions with the ligands angiopoietin (Ang) 1, Ang2, VEGF and FGF.8 Ang1 and 2 are angiogenic factors that have divergent effects on binding to TIE2 and are modulated by the presence or absence of VEGF and FGF.12 Constitutive Ang1 expression is found in pericytes, smooth muscle cells, fibroblasts and some tumor cells, while Ang2 expression is tightly controlled and almost exclusively expressed by endothelial cells.11 Expression studies have shown that Ang2 and/or VEGF are upregulated in a variety of human tumor samples, including endometrial adenocarcinoma, bladder cancer and gastric cancer, and suggest that the balance between Ang1 and Ang2 is important in neoangiogenesis.13–15

In addition to upregulation associated with VEGF signaling, FGFR signaling appears to upregulate Ang2 expression and reduce Ang1, thus promoting tumor vascular disruption via TIE2.9 This, in combination with FGFR-stimulated upregulation of VEGF expression in tumors, highlights the potential for FGFR signaling to stimulate the development of abnormal tumor vasculature.

FGFR signaling plays a key role in many functions including cell proliferation, survival and migration, and can promote cancer development by affecting a range of major downstream processes.16 An emerging body of evidence has identified roles for FGFR signaling in oncogenic processes, including proliferation, survival, migration and angiogenesis.16

The receptor tyrosine kinases (RTKs) RET and KIT represent valid targets for cancer therapy. Activating mutations of the RET gene have been identified as driving oncogenic events in subsets of thyroid carcinomas, and the presence of oncogenic KIT mutations in GIST is well documented.17, 18

In this report, we provide data characterizing the biochemical and in vitro cellular activity, and in vivo antitumor efficacy, of regorafenib (BAY 73-4506; Bayer Schering Pharma AG, Berlin, Germany). This novel oral multikinase inhibitor possesses a distinct profile targeting angiogenic, stromal and oncogenic RTKs. Regorafenib demonstrated very robust antitumor and antiangiogenic activity in a panel of tumor models that support its clinical development.