title: Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors.
abstract: The mammalian target of rapamycin (mTOR) pathway is implicated widely in cancer pathophysiology. Dual inhibition of the mTOR kinase complexes mTORC1 and mTORC2 decreases tumor xenograft growth in vivo and VEGF secretion in vitro, but the relationship between these two effects are unclear. In this study, we examined the effects of mTORC1/2 dual inhibition on VEGF production, tumor angiogenesis, vascular regression, and vascular regrowth, and we compared the effects of dual inhibition to mTORC1 inhibition alone. ATP-competitive inhibitors OSI-027 and OXA-01 targeted both mTORC1 and mTORC2 signaling in vitro and in vivo, unlike rapamycin that only inhibited mTORC1 signaling. OXA-01 reduced VEGF production in tumors in a manner associated with decreased vessel sprouting but little vascular regression. In contrast, rapamycin exerted less effect on tumoral production of VEGF. Treatment with the selective VEGFR inhibitor OSI-930 reduced vessel sprouting and caused substantial vascular regression in tumors. However, following discontinuation of OSI-930 administration tumor regrowth could be slowed by OXA-01 treatment. Combining dual inhibitors of mTORC1 and mTORC2 with a VEGFR2 inhibitor decreased tumor growth more than either inhibitor alone. Together, these results indicate that dual inhibition of mTORC1/2 exerts antiangiogenic and antitumoral effects that are even more efficacious when combined with a VEGFR antagonist.
authors.affiliation: Cardiovascular Research Institute, Comprehensive Cancer Center, and Department of Anatomy, University of California, San Francisco, California 94143-0452, USA.
authors.forename: Beverly L
authors.initials: BL
authors.lastname: Falcon
authors.forename: Sharon
authors.initials: S
authors.lastname: Barr
authors.forename: Prafulla C
authors.initials: PC
authors.lastname: Gokhale
authors.forename: Jeyling
authors.initials: J
authors.lastname: Chou
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fogarty
authors.forename: Philippe
authors.initials: P
authors.lastname: Depeille
authors.forename: Mark
authors.initials: M
authors.lastname: Miglarese
authors.forename: David M
authors.initials: DM
authors.lastname: Epstein
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D007150:Immunohistochemistry; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D046912:Multiprotein Complexes; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013876:Thiophenes / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C493245:CRTC2 protein, human; D046912:Multiprotein Complexes; C505207:OSI 930; D011506:Proteins; D011804:Quinolines; D013876:Thiophenes; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus