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

共 78 条

[1] ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo [J].

Ackler, Scott ;

Xiao, Yu ;

Mitten, Michael J. ;

Foster, Kelly ;

Oleksijew, Anatol ;

Refici, Marion ;

Schlessinger, Sally ;

Wang, Baole ;

Chemburkar, Sanjay R. ;

Bauch, Joy ;

Tse, Christin ;

Frost, David J. ;

Fesik, Stephen W. ;

Rosenberg, Saul H. ;

Elmore, Steven W. ;

Shoemaker, Alex R. .

MOLECULAR CANCER THERAPEUTICS, 2008, 7 (10) :3265-3274

[2] Initiation Factor eIF2-independent Mode of c-Src mRNA Translation Occurs via an Internal Ribosome Entry Site [J].

Allam, Heba ;

Ali, Naushad .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (08) :5713-5725

[3] Targeting the Phosphoinositide-3 (PI3) Kinase Pathway in Breast Cancer [J].

Baselga, Jose .

ONCOLOGIST, 2011, 16 :12-19

[4] A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer [J].

Braunstein, Steve ;

Karpisheva, Ksenia ;

Pola, Carolina ;

Goldberg, Judith ;

Hochman, Tsivia ;

Yee, Herman ;

Cangiarella, Joan ;

Arju, Rezina ;

Formenti, Silvia C. ;

Schneider, Robert J. .

MOLECULAR CELL, 2007, 28 (03) :501-512

[5] Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor [J].

Brunet, A ;

Bonni, A ;

Zigmond, MJ ;

Lin, MZ ;

Juo, P ;

Hu, LS ;

Anderson, MJ ;

Arden, KC ;

Blenis, J ;

Greenberg, ME .

CELL, 1999, 96 (06) :857-868

[6] A transforming mutation in the pleckstrin homology domain of AKT1 in cancer [J].

Carpten, John D. ;

Faber, Andrew L. ;

Horn, Candice ;

Donoho, Gregory P. ;

Briggs, Stephen L. ;

Robbins, Christiane M. ;

Hostetter, Galen ;

Boguslawski, Sophie ;

Moses, Tracy Y. ;

Savage, Stephanie ;

Uhlik, Mark ;

Lin, Aimin ;

Du, Jian ;

Qian, Yue-Wei ;

Zeckner, Douglas J. ;

Tucker-Kellogg, Greg ;

Touchman, Jeffrey ;

Patel, Ketan ;

Mousses, Spyro ;

Bittner, Michael ;

Schevitz, Richard ;

Lai, Mei-Huei T. ;

Blanchard, Kerry L. ;

Thomas, James E. .

NATURE, 2007, 448 (7152) :439-U1

[7]

Carracedo A, 2008, J CLIN INVEST, V118, P3065, DOI [10.1172/JCI34739, 10.1172/jCI34739]

[8] AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity [J].

Chandarlapaty, Sarat ;

Sawai, Ayana ;

Scaltriti, Maurizio ;

Rodrik-Outmezguine, Vanessa ;

Grbovic-Huezo, Olivera ;

Serra, Violeta ;

Majumder, Pradip K. ;

Baselga, Jose ;

Rosen, Neal .

CANCER CELL, 2011, 19 (01) :58-71

[9] Anoikis: A necessary death program for anchorage-dependent cells [J].

Chiarugi, Paola ;

Giannoni, Elisa .

BIOCHEMICAL PHARMACOLOGY, 2008, 76 (11) :1352-1364

[10] Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation [J].

Choo, Andrew Y. ;

Yoon, Sang-Oh ;

Kim, Sang Gyun ;

Roux, Philippe P. ;

Blenis, John .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (45) :17414-17419

← 1 2 3 4 5 6 7 8 →