Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells

被引：326

作者：

Muranen, Taru ^{[1
]}

Selfors, Laura M. ^{[1
]}

Worster, Devin T. ^{[1
]}

Iwanicki, Marcin P. ^{[1
]}

Song, Loling ^{[1
]}

Morales, Fabiana C. ^{[2
]}

Gao, Sizhen ^{[1
]}

Mills, Gordon B. ^{[2
]}

Brugge, Joan S. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

来源：

CANCER CELL | 2012年 / 21卷 / 02期

基金：

芬兰科学院;

关键词：

CAP-INDEPENDENT TRANSLATION; SIGNALING PATHWAYS; TUMOR-SUPPRESSOR; INSULIN-RECEPTOR; AKT ACTIVATION; UP-REGULATION; PI3K PATHWAY; BREAST; INITIATION; APOPTOSIS;

D O I：

10.1016/j.ccr.2011.12.024

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The PI3K/mTOR-pathway is the most commonly dysregulated pathway in epithelial cancers and represents an important target for cancer therapeutics. Here, we show that dual inhibition of PI3K/mTOR in ovarian cancer-spheroids leads to death of inner matrix-deprived cells, whereas matrix-attached cells are resistant. This matrix-associated resistance is mediated by drug-induced upregulation of cellular survival programs that involve both FOXO-regulated transcription and cap-independent translation. Inhibition of any one of several upregulated proteins, including BcI-2, EGFR, or IGF1R, abrogates resistance to PI3K/mTOR inhibition. These results demonstrate that acute adaptive responses to PI3K/mTOR inhibition in matrix-attached cells resemble well-conserved stress responses to nutrient and growth factor deprivation. Bypass of this resistance mechanism through rational design of drug combinations could significantly enhance PI3K-targeted drug efficacy.

引用

页码：227 / 239

页数：13

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