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.