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Sci. Signal., 9 November 2010
Vol. 3, Issue 147, p. ra81
[DOI: 10.1126/scisignal.2001017]

RESEARCH ARTICLES

Editor's Summary

Blocking All Escape Routes
Many cancers, including glioma, are associated with increased signaling through the phosphatidylinositol 3-kinase to Akt to mammalian target of rapamycin (PI3K-Akt-mTOR) pathway, which promotes cell growth, proliferation, and survival. This suggests that pharmacological inhibition of key kinases in this pathway could provide an approach to antineoplastic therapy. Disappointingly, however, inhibitors of PI3K, Akt, or mTOR typically block cancer cell growth rather than eliciting the death of malignant cells, limiting their utility as antineoplastic agents. Noting that autophagy, a process of autodigestion that can enable cells to endure periods of stress and nutrient deprivation, could provide a survival mechanism under conditions of decreased PI3K-Akt-mTOR signaling, Fan et al. explored the effects of various combinations of kinase and autophagy inhibitors on glioma cell survival. Inhibition of mTOR complex 1 (mTORC1) with rapamycin induced autophagy; however, cells survived the combination of rapamycin with inhibitors of autophagy by activating Akt signaling. In contrast, the combined inhibition of mTORC1, PI3K, and autophagy, or that of mTORC1, mTORC2, and autophagy, triggered apoptosis—the process of programmed cell death. The authors elicited cell death with combinations of drugs that are either now in use in patients or in clinical trials, raising the hope that this approach could be readily translatable to human therapy.

Citation: Q.-W. Fan, C. Cheng, C. Hackett, M. Feldman, B. T. Houseman, T. Nicolaides, D. Haas-Kogan, C. D. James, S. A. Oakes, J. Debnath, K. M. Shokat, W. A. Weiss, Akt and Autophagy Cooperate to Promote Survival of Drug-Resistant Glioma. Sci. Signal. 3, ra81 (2010).

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