Inactivation Of Endothelial Cell Phosphoinositide 3-Kinase Beta Inhibits Tumor Angiogenesis And Tumor Growth

Angiogenesis inhibitors, such as the receptor tyrosine kinase (RTK) inhibitor sunitinib, target vascular endothelial growth factor (VEGF) signaling in cancers. However, only a fraction of patients respond, and most ultimately develop resistance to current angiogenesis inhibitor therapies. Activity of alternative pro-angiogenic growth factors, acting via RTK or G-protein coupled receptors (GPCR), may mediate VEGF inhibitor resistance. The phosphoinositide 3-kinase (PI3K)beta isoform is uniquely coupled to both RTK and GPCRs. We investigated the role of endothelial cell (EC) PI3K beta in tumor angiogenesis. Pro-angiogenic GPCR ligands were expressed by patient-derived renal cell carcinomas (PD-RCC), and selective inactivation of PI3K beta reduced PD-RCC-stimulated EC spheroid sprouting. EC-specific PI3K beta knockout (Epsilon C-beta KO) in mice potentiated the sunitinib-induced reduction in subcutaneous growth of LLC1 and B16F10, and lung metastasis of B16F10 tumors. Compared to single-agent sunitinib treatment, tumors in sunitinib-treated Epsilon C-beta KO mice showed a marked decrease in microvessel density, and reduced new vessel formation. The fraction of perfused mature tumor microvessels was increased in Epsilon C-beta KO mice suggesting immature microvessels were most sensitive to combined sunitinib and PI3K beta inactivation. Taken together, EC PI3K beta inactivation with sunitinib inhibition reduces microvessel turnover and decreases heterogeneity of the tumor microenvironment, hence PI3K beta inhibition may be a useful adjuvant antiangiogenesis therapy with sunitinib.