Investigating the Cause of Mortality by Systemic Akt Isoforms Deletion

The PI3K and its downstream effector, the serine-threonine kinase AKT frequently display hyperactivity in cancer, leading to the development of various PI3K and AKT inhibitors. Despite the fact that deletion of the three Akt isoforms (Akt1, Akt2, and Akt3) either individually or in combination yields distinct phenotypes, there remains a lack of AKT isoform-specific inhibitors. The pan PI3K and AKT inhibitors display different levels of toxicity. Trying to assess the efficacy and toxicity of Akt inhibitors by genetic deletion of Akt isoforms, we showed that systemic deletion of Akt1 and Akt2 in adult mice elicits rapid mortality. The mice showed a swift body weight reduction, intestinal damage, and rapid mortality, however, the precise underlying mechanisms remain to be elucidated. Here we identified that the primary cause of these adverse effects is the loss of the self-renewing Lgr5+ stem cells from the crypt of the small intestine and lack of intestinal epithelial barrier integrity. Consistently, we confirmed that specific deletion of Akt1 and Akt2 in the crypt/villus region recapitulates the systemic deletion phenotype, leading to severe intestinal damage and loss of body weight. As a consequence of intestinal damage, there is a permeabilization of the epithelial barrier, followed by bacterial infection, inflammation, immune cell infiltration, and rapid mortality. Meanwhile, pharmacological inhibition of PI3K or Akt activity yielded similar results. Mechanistically, we found that the intestinal damage mediated by Akt1 and Akt2 deletion is FoxO dependent and can be reversed by additional deletion of the cell death inducer FoxO1. Furthermore, we revealed that hyperactivation of mTORC1 is sufficient to induce the viability, proliferation, and differentiation of stem cells in the absence of Akt1 and Akt2. Thus, deletion of Tsc1 can preserve tissue homeostasis and promote survival, independent of Akt. In summary, our findings demonstrate that intestinal deletion of Akt is lethal and that deletion of FoxO1 or hyperactivation of mTORC1 is sufficient for intestinal stem cell maintenance, tissue homeostasis, and mouse viability. We speculate that the intestinal damage may cause severe diarrhea in patients treated with pan-PI3K or pan-Akt inhibitors.