Although the
phosphatidylinositol 3-kinase to Akt to
mammalian target of rapamycin (PI3K-Akt-mTOR) pathway promotes survival signaling, inhibitors of PI3K and mTOR induce minimal cell death in
PTEN (phosphatase and
tensin homolog deleted from chromosome 10) mutant
glioma. Here, we show that the dual PI3K-mTOR inhibitor
PI-103 induces autophagy in a form of
glioma that is resistant to
therapy. Inhibitors of autophagosome maturation cooperated with
PI-103 to induce apoptosis through the mitochondrial pathway, indicating that the cellular self-digestion process of autophagy acted as a survival signal in this setting. Not all inhibitors of mTOR synergized with inhibitors of autophagy.
Rapamycin delivered alone induced autophagy, yet cells survived inhibition of autophagosome maturation because of
rapamycin-mediated activation of Akt. In contrast,
adenosine 5'-triphosphate-competitive inhibitors of mTOR stimulated autophagy more potently than did
rapamycin, with inhibition of mTOR complexes 1 and 2 contributing independently to induction of autophagy. We show that combined inhibition of PI3K and mTOR, which activates autophagy without activating Akt, cooperated with inhibition of autophagy to cause
glioma cells to undergo apoptosis. Moreover, the PI3K-mTOR inhibitor
NVP-BEZ235, which is in clinical use, synergized with the lysosomotropic inhibitor of autophagy,
chloroquine, another agent in clinical use, to induce apoptosis in
glioma xenografts in vivo, providing a therapeutic approach potentially translatable to humans.