Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer

被引：1104

作者：

Carver, Brett S. ^{[1
,2
,3
]}

Chapinski, Caren ^{[1
,2
,3
]}

Wongvipat, John ^{[1
]}

Hieronymus, Haley ^{[1
]}

Chen, Yu ^{[1
,4
]}

Chandarlapaty, Sarat ^{[4
]}

Arora, Vivek K. ^{[1
,4
]}

Le, Carl ^{[5
]}

Koutcher, Jason ^{[4
,5
]}

Scher, Howard ^{[4
]}

Scardino, Peter T. ^{[2
,3
]}

Rosen, Neal ^{[4
]}

Sawyers, Charles L. ^{[1
,4
,6
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Div Urol, New York, NY 10065 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Med Phys, New York, NY 10065 USA

[6] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA

来源：

CANCER CELL | 2011年 / 19卷 / 05期

关键词：

DUAL PI3K/MTOR INHIBITOR; HORMONAL-THERAPY; TUMOR-SUPPRESSOR; PATHWAY; KINASE; MTOR; CELLS; INDUCTION; TARGET; PHOSPHATASE;

D O I：

10.1016/j.ccr.2011.04.008

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Prostate 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.

引用

页码：575 / 586

页数：12

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