Activated FGF2 signaling pathway in tumor vasculature is essential for acquired resistance to anti-VEGF therapy

Abstract

Anti-vascular endothelial growth factor (VEGF) therapy shows antitumor activity against various types of solid cancers. Several resistance mechanisms against anti-VEGF therapy have been elucidated; however, little is known about the mechanisms by which the acquired resistance arises. Here, we developed new anti-VEGF therapy-resistant models driven by chronic expression of the mouse VEGFR2 extracellular domain fused with the human IgG4 fragment crystallizable (Fc) region (VEGFR2-Fc). In the VEGFR2-Fc-expressing resistant tumors, we demonstrated that the FGFR2 signaling pathway was activated, and pericytes expressing high levels of FGF2 were co-localized with endothelial cells. Lenvatinib, a multiple tyrosine kinase inhibitor including VEGFR and FGFR inhibition, showed marked antitumor activity against VEGFR2-Fc-expressing resistant tumors accompanied with a decrease in the area of tumor vessels and suppression of phospho-FGFR2 in tumors. Our findings reveal the key role that intercellular FGF2 signaling between pericytes and endothelial cells plays in maintaining the tumor vasculature in anti-VEGF therapy-resistant tumors.Anti-vascular endothelial growth factor (VEGF) therapy, such as anti-VEGF antibody (Ab), anti-VEGFR2 Ab, and multiple tyrosine kinase inhibitors (TKIs) targeting VEGFR2, has been used to treat various types of solid cancers for over a decade. Despite massive efforts, the mechanisms of acquired resistance to anti-VEGF therapy are still not completely understood 1,2 .Other angiogenic factors such as fibroblast growth factors (FGFs) 3,4 , angiopoietins 5,6 , and platelet-derived growth factors (PDGFs) 7-9 have been reported to induce tumor angiogenesis as a single factor or in crosstalk with VEGF 10 . Upregulation of FGFs by chronic anti-VEGF therapy has been reported in the RIP1-Tag2 mouse (a pancreatic neuroendocrine tumor model) treated by DC101 (an anti-VEGFR2 Ab) 11 , and in a human head and neck squamous cell carcinoma xenograft tumor model treated by bevacizumab (an anti-VEGFA Ab) 12 . In a study of MCaIV syngeneic tumor models, cancer-associated fibroblasts and adipocytes expressed FGF2 and mediated resistance to anti-mouse VEGF Ab B20 13 . In addition, in the Y-MESO-14 (human malignant pleural mesothelioma cell line) xenograft tumor model, fibrocyte-like cells mediated the resistance to bevacizumab by producing FGF2 14 . In contrast, concurrent inhibition of VEGFR and FGFR by a chimeric dual decoy receptor enhanced antitumor activity in A549 (human lung cancer cell line) and Caki-1 (human renal cancer cell line) xenograft tumor models 15 . These results suggest that the FGF signaling pathway contributes to resistance to anti-VEGF therapy; however, it is largely unknown how the FGF signaling pathway becomes activated when tumors acquire resistance to anti-VEGF therapy. Recently, the role of the VEGF signaling pathway in cancer immunity has received increased attention because of the promising combination antitumor activity of anti-VEGF therapy with immune checkpoint inhibitors in pre-clinica...

From CENTRAL to SENTRAL (SErum aNgiogenesis cenTRAL): Circulating Predictive Biomarkers to Anti-VEGFR Therapy

“…Ichikawa et al reported that in cell lines and in an animal model that acquired resistance to anti-VEGF-based therapy is associated with a similar over-expression of both FGF-2 and vascular endothelial growth factor receptor-2 (FGFR-2). Tumor over-expressing the mouse VEGFR2 extracellular domain fused with the human IgG4 fragment crystallizable (Fc) region (VEGFR-2-Fc) showed highest levels of mRNA expression from FGF2 and other factors of FGF-2/FGFR-2 pathway [34]. Finally, in ovarian cancer resistant to bevacizumab, Guerrouehan et al demonstrated that Protein Kinase B (PKB also known as AKT)-mediated endothelial factors secretion (where FGF-2 plays a major role) creates an autocrine loop that avoids bevacizumab inhibition.…”

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

“…FGF2 is also overexpressed in subtypes of bladder cancer, and is associated with promoting migration, angiogenesis and invasiveness [ 141 , 142 ]. FGF2 expression by tumor vasculature pericytes has also been identified as a mechanism of anti-vascular endothelial growth factor receptor (VEGFR) resistance [ 143 ]. FGF2 is an angiogenic factor in multiple myeloma (MM) that positively regulates expression of growth and survival interleukin-6 (IL-6) in a reciprocal manner [ 144 ].…”

Resistance to Molecularly Targeted Therapies in Melanoma

“…Additionally, VEGF xxx b isoforms inhibits the angiogenic activity of VEGF and may be effective in anti-cancer therapy [ 186 ]. In a study using VEGFR2-Fc-resistant murine melanoma models, the FGF2 signaling pathway was found to play a key role between endothelial cells and pericytes in maintaining tumor vasculature in acquired anti-VEGF-resistant tumors [ 187 ].…”