PDK1-SGK1 Signaling Sustains AKT-Independent mTORC1 Activation and Confers Resistance to PI3Kα Inhibition

被引：186

作者：

Castel, Pau ^{[1
]}

Ellis, Haley ^{[1
]}

Bago, Ruzica ^{[2
]}

Toska, Eneda ^{[1
]}

Razavi, Pedram ^{[1
,3
]}

Carmona, F. Javier ^{[1
]}

Kannan, Srinivasaraghavan ^{[4
]}

Verma, Chandra S. ^{[4
,5
,6
]}

Dickler, Maura ^{[3
]}

Chandarlapaty, Sarat ^{[1
,3
]}

Brogi, Edi ^{[7
]}

Alessi, Dario R. ^{[2
]}

Baselga, Jose ^{[1
,3
]}

Scaltriti, Maurizio ^{[1
,7
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, HOPP, 1275 York Ave,Box 20, New York, NY 10065 USA

[2] Univ Dundee, Coll Life Sci, MRC Prot Phosphorylat & Ubiquitylat Unit, Dow St, Dundee DD1 5EH, Scotland

[3] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave,Box 20,Suite M2015, New York, NY 10065 USA

[4] Bioinformat Inst A STAR, 30 Biopolis St,07-01 Matrix, Singapore 138671, Singapore

[5] Nanyang Technol Univ, Sch Biol Sci, 60 Nanyang Dr, Singapore 637551, Singapore

[6] Natl Univ Singapore, Dept Biol Sci, 14 Sci Dr 4, Singapore 117543, Singapore

[7] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave,Box 20, New York, NY 10065 USA

来源：

CANCER CELL | 2016年 / 30卷 / 02期

基金：

英国医学研究理事会;

关键词：

PROTEIN-KINASE; TUBEROUS SCLEROSIS; CANCER CELLS; PHOSPHORYLATION; COMPLEX; TSC2; GROWTH; SERUM; PDK1; AKT/PKB;

D O I：

10.1016/j.ccell.2016.06.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

PIK3CA, which encodes the p110 alpha subunit of PI3K, is frequently mutated and oncogenic in breast cancer. PI3K alpha inhibitors are in clinical development and despite promising early clinical activity, intrinsic resistance is frequent among patients. We have previously reported that residual downstream mTORC1 activity upon treatment with PI3K alpha inhibitors drives resistance to these agents. However, the mechanism underlying this phenotype is not fully understood. Here we show that in cancer cells resistant to PI3K alpha inhibition, PDK1 blockade restores sensitivity to these therapies. SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2. Targeting either PDK1 or SGK1 prevents mTORC1 activation, restoring the antitumoral effects of PI3Ka inhibition in resistant cells.

引用

页码：229 / 242

页数：14

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