Author/Authors :
Carver، نويسنده , , Brett S. and Chapinski، نويسنده , , Caren and Wongvipat، نويسنده , , John and Hieronymus، نويسنده , , Haley and Chen، نويسنده , , Yu and Chandarlapaty، نويسنده , , Sarat and Arora، نويسنده , , Vivek K. and Le، نويسنده , , Carl and Koutcher، نويسنده , , Jason and Scher، نويسنده , , Howard and Scardino، نويسنده , , Peter T. and Rosen، نويسنده , , Neal and Sawyers، نويسنده , , Charles L.، نويسنده ,
Abstract :
Summary
te cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.
