BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2.
Most anti-angiogenic therapies currently being evaluated in clinical trials targetvascular endothelial growth factor (VEGF) pathway; however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other potential therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here we identified BRAF kinase inhibitor, vemurafenibas an agent with potential anti-angiogenic and anti-breast cancer activities. Vemurafenib demonstrated inhibition of endothelial cell proliferation, migration, and tube formation in response to basic fibroblast growth factor (bFGF). In ex vivo and in vivo angiogenesis assays, vemurafenib suppressed bFGF-induced microvessel sprouting of rat aortic rings and angiogenesis in vivo. To understand the underlying molecular basis, we examined the effects of vemurafenib on different molecular components in treated endothelial cell, and found that vemurafenib suppressed bFGF-triggered activation of FGFR2 and protein kinase B (AKT). Moreover, vemurafenib directly inhibited proliferation and blocked the oncogenic signaling pathways in breast cancer cell. In vivo, using xenograft models of breast cancer cells MDA-MB-231, vemurafenib showed growth-inhibitory activity associated with inhibition of tumor angiogenesis. Taken together, our results indicate that vemurafenib targets the FGFR2-mediated AKT signaling pathway in endothelial cells, leading to the suppression of tumor growth and angiogenesis.
Department of Clinical Laboratory, Huzhou Central Hospital No. 198, Hongqi Road, Huzhou 313000, Zhejiang Province, China.
Zong Xin
ZX
Zhang
Department of Clinical Laboratory, Huzhou Central Hospital No. 198, Hongqi Road, Huzhou 313000, Zhejiang Province, China.
Wen Jun
WJ
Jin
Department of Breast Medical Care, Huzhou Maternity and Child Health Care Hospital Wuxing District, East Street 2, Huzhou 313000, Zhejiang Province, China.
Sheng
S
Yang
Department of Breast Medical Care, Huzhou Maternity and Child Health Care Hospital Wuxing District, East Street 2, Huzhou 313000, Zhejiang Province, China.
Cun Li
CL
Ji
FGFR2; Vemurafenib; angiogenesis; breast cancer