Feedback Suppression of PI3Kα Signaling in PTEN-Mutated Tumors Is Relieved by Selective Inhibition of PI3Kβ

被引：191

作者：

Schwartz, Sarit ^{[1
]}

Wongvipat, John ^{[2
]}

Trigwell, Cath B. ^{[4
]}

Hancox, Urs ^{[4
]}

Carver, Brett S. ^{[2
]}

Rodrik-Outmezguine, Vanessa ^{[1
]}

Will, Marie ^{[1
]}

Yellen, Paige ^{[1
]}

de Stanchina, Elisa ^{[1
]}

Baselga, Jose ^{[2
]}

Scher, Howard I. ^{[3
]}

Barry, Simon T. ^{[4
]}

Sawyers, Charles L. ^{[2
]}

Chandarlapaty, Sarat ^{[2
,3
,5
]}

Rosen, Neal ^{[1
,5
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA

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

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

[4] AstraZeneca, Macclesfield SK10 4TG, Cheshire, England

[5] Weill Cornell Med Coll, New York, NY 10065 USA

来源：

CANCER CELL | 2015年 / 27卷 / 01期

关键词：

ADAPTIVE RESISTANCE; PI3K INHIBITOR; BREAST-CANCER; RECEPTOR; KINASE; GROWTH; RAS; ACTIVATION; IDELALISIB; P110-ALPHA;

D O I：

10.1016/j.ccell.2014.11.008

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

In PTEN-mutated tumors, we show that PI3K alpha activity is suppressed and PI3K signaling is driven by PI3K beta. A selective inhibitor of PI3K beta inhibits the Akt/mTOR pathway in these tumors but not in those driven by receptor tyrosine kinases. However, inhibition of PI3K beta only transiently inhibits Akt/mTOR signaling because it relieves feedback inhibition of IGF1R and other receptors and thus causes activation of PI3K alpha and a rebound in downstream signaling. This rebound is suppressed and tumor growth inhibition enhanced with combined inhibition of PI3K alpha and PI3K beta. In PTEN-deficient models of prostate cancer, this effective inhibition of PI3K causes marked activation of androgen receptor activity. Combined inhibition of both PI3K isoforms and androgen receptor results in major tumor regressions.

引用

页码：109 / 122

页数：14

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