mTOR inhibition (rapamycin/RAD001) reverses Akt-driven prostate intraepithelial neoplasia in mice.
| Evidence tier | C Animal in vivo |
| Study type | 4 - Animal Study |
| Model system | Mouse (prostate) |
| Journal | Nature medicine |
| Year | 2004 |
| Peer reviewed | Yes |
| Source | DOI 10.1038/nm1052 · PMID 15156201 |
Loss of PTEN function leads to activation of phosphoinositide 3-kinase (PI3K) signaling and Akt. Clinical trials are now testing whether mammalian target of rapamycin (mTOR) inhibition is useful in treating PTEN-null cancers. Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis. Thus, there is an mTOR-dependent survival signal required downstream of Akt. Bcl2 expression, however, only partially restored intraluminal cell growth in the setting of mTOR inhibition. Expression profiling showed that Hif-1 alpha targets, including genes encoding most glycolytic enzymes, constituted the dominant transcriptional response to AKT activation and mTOR inhibition. These data suggest that the expansion of AKT-driven prostate epithelial cells requires mTOR-dependent survival signaling and activation of HIF-1 alpha, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1 alpha activity.
| Intervention | mTOR inhibition (rapamycin) |
| Target | mTOR / Akt / HIF-1 |
| Model | Mouse (prostate, AKT1 transgenic) |
| Effect | mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia via apoptotic and HIF-1-dependent pathways |