Autophagy, an Achilles' heel AKTing against cancer?
Akt has emerged as an attractive cancer therapeutic target with a central role in cell survival, growth, proliferation and metabolism.A key to the clinical success of Akt inhibitors is the maximal possible antitumor efficacy achievable without intolerable side effects. In our recent work, we show that although Akt inhibition does not always induce a clear apoptotic response, autophagy is a more readily detectable response to pan-Akt knockdown or selective small molecule inhibitors of the PI3K/Akt pathway. Autophagy isa catabolic process of bulk lysosomal degradation and recycling of cytoplasmic material and organelles, which can provide a temporary survival mechanism for cells under stress conditions, but can also make cells vulnerable to several forms of cell death under specific circumstances. We hypothesize that autophagy induced by Akt inhibition may sensitize tumor cells to agents targeting the later steps of this lysosomal degradation process. Indeed, agents that interfere with the lysosomal degradation function could precipitate cell death when combined with Akt inhibition and promote complete tumor remissions in preclinical models. These findings suggest that manipulating the autophagic response may be a promising strategy to increase the therapeutic efficacy of Akt inhibitors.
Degtyarev
Michael
M
Department of Cancer Signaling and Translational Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
De Mazière
Ann
A
Klumperman
Judith
J
Lin
Kui
K
D000818:Animals; D001343:Autophagy; D016923:Cell Death; D045744:Cell Line, Tumor; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt