Inactivation of endothelial cell phosphoinositide 3-kinase β inhibits tumor angiogenesis and tumor growth.

Abstract

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)β isoform is uniquely coupled to both RTK and GPCRs. We investigated the role of endothelial cell (EC) PI3Kβ in tumor angiogenesis. Pro-angiogenic GPCR ligands were expressed by patient-derived renal cell carcinomas (PD-RCC), and selective inactivation of PI3Kβ reduced PD-RCC-stimulated EC spheroid sprouting. EC-specific PI3Kβ knockout (ΕC-βKO) 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 ΕC-βKO mice showed a marked decrease in microvessel density, and reduced new vessel formation. The fraction of perfused mature tumor microvessels was increased in ΕC-βKO mice suggesting immature microvessels were most sensitive to combined sunitinib and PI3Kβ inactivation. Taken together, EC PI3Kβ inactivation with sunitinib inhibition reduces microvessel turnover and decreases heterogeneity of the tumor microenvironment, hence PI3Kβ inhibition may be a useful adjuvant antiangiogenesis therapy with sunitinib.

• Authors: Abul K Azad, Pavel Zhabyeyev, Bart Vanhaesebroeck, Gary Eitzen, Gavin Y Oudit, Ronald B Moore, Allan G Murray
• Journal: Oncogene (Oncogene) Vol. 39 Issue 41 Pg. 6480-6492 (10 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 32879446 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Morpholines
• Protein Kinase Inhibitors
• Pyrimidinones
• TGX 221
• Thiazoles
• Alpelisib
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• PIK3CB protein, human
• Pik3ca protein, mouse
• Pik3cb protein, mouse
• Kdr protein, mouse
• Vascular Endothelial Growth Factor Receptor-2
• Sunitinib

Topics

• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (antagonists & inhibitors, pharmacology, therapeutic use)
• Carcinoma, Renal Cell (blood supply, drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Class I Phosphatidylinositol 3-Kinases (antagonists & inhibitors, genetics, metabolism)
• Endothelium, Vascular (cytology, pathology)
• Human Umbilical Vein Endothelial Cells
• Humans
• Kidney Neoplasms (blood supply, drug therapy, pathology)
• Melanoma, Experimental (blood supply, drug therapy, pathology)
• Mice, Knockout
• Microvessels (drug effects, pathology)
• Morpholines (pharmacology, therapeutic use)
• Neovascularization, Pathologic (drug therapy, pathology)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Pyrimidinones (pharmacology, therapeutic use)
• Sunitinib (pharmacology, therapeutic use)
• Thiazoles (pharmacology, therapeutic use)
• Tumor Microenvironment (drug effects)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, metabolism)