PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer

被引:269
作者
Bosch, Ana [1 ]
Li, Zhiqiang [1 ]
Bergamaschi, Anna [2 ]
Ellis, Haley [1 ]
Toska, Eneda [1 ]
Prat, Aleix [3 ,4 ]
Tao, Jessica J. [5 ]
Spratt, Daniel E. [6 ]
Viola-Villegas, Nerissa T. [6 ]
Castel, Pau [1 ]
Minuesa, Gerard [7 ]
Morse, Natasha [1 ]
Rodon, Jordi [8 ,9 ]
Ibrahim, Yasir [10 ]
Cortes, Javier [8 ]
Perez-Garcia, Jose [8 ]
Galvan, Patricia
Grueso, Judit [10 ]
Guzman, Marta [10 ]
Katzenellenbogen, John A. [11 ]
Kharas, Michael
Lewis, Jason S. [6 ]
Dickler, Maura
Serra, Violeta [10 ]
Rosen, Neal
Chandarlapaty, Sarat [1 ,12 ,13 ,14 ,15 ,16 ]
Scaltriti, Maurizio [1 ,14 ]
Baselga, Jose [1 ,12 ,13 ,15 ,16 ]
机构
[1] Human Oncol & Pathogenesis Program, New York, NY 10065 USA
[2] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA
[3] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA
[4] VHIO, Translat Genom Grp, Barcelona 08035, Spain
[5] Hosp Clin Barcelona, August Pi & Sunyer Biomed Res Inst, Translat Genom & Targeted Therapeut Solid Tumors, Barcelona 08035, Spain
[6] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA
[7] Harvard Univ, Sch Med, Charlestown, MA 02129 USA
[8] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA
[9] Mem Sloan Kettering Canc Ctr, Mol Pharmacol & Chem Program, New York, NY 10065 USA
[10] Mem Sloan Kettering Canc Ctr, Ctr Cell Engn, New York, NY 10065 USA
[11] VHIO, Dept Med Oncol, Barcelona 08035, Spain
[12] Univ Autonoma Barcelona, Bellaterra 08193, Spain
[13] VHIO, Expt Therapeut Grp, Barcelona 08035, Spain
[14] Univ Illinois, Dept Chem, Urbana, IL 61801 USA
[15] Mem Sloan Kettering Canc Ctr, Dept Med, Breast Med Serv, New York, NY 10065 USA
[16] Weill Cornell Med Coll, New York, NY 10065 USA
基金
欧洲研究理事会;
关键词
GENE-EXPRESSION; RESISTANCE; MUTATIONS; GROWTH; ALPHA; TRANSCRIPTION; DEPRIVATION; FULVESTRANT; REPRESSION; SUBSET;
D O I
10.1126/scitranslmed.aaa4442
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase alpha (PI3K alpha) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of up-regulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3K alpha inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3K alpha inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.
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收藏
页数:11
相关论文
共 45 条
[1]   Everolimus in Postmenopausal Hormone-Receptor-Positive Advanced Breast Cancer [J].
Baselga, Jose ;
Campone, Mario ;
Piccart, Martine ;
Burris, Howard A., III ;
Rugo, Hope S. ;
Sahmoud, Tarek ;
Noguchi, Shinzaburo ;
Gnant, Michael ;
Pritchard, Kathleen I. ;
Lebrun, Fabienne ;
Beck, J. Thaddeus ;
Ito, Yoshinori ;
Yardley, Denise ;
Deleu, Ines ;
Perez, Alejandra ;
Bachelot, Thomas ;
Vittori, Luc ;
Xu, Zhiying ;
Mukhopadhyay, Pabak ;
Lebwohl, David ;
Hortobagyi, Gabriel N. .
NEW ENGLAND JOURNAL OF MEDICINE, 2012, 366 (06) :520-529
[2]   Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice [J].
Brachmann, SM ;
Ueki, K ;
Engelman, JA ;
Kahn, RC ;
Cantley, LC .
MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (05) :1596-1607
[3]   The phosphoinositide 3-kinase pathway [J].
Cantley, LC .
SCIENCE, 2002, 296 (5573) :1655-1657
[4]  
Carracedo A, 2008, J CLIN INVEST, V118, P3065, DOI [10.1172/jCI34739, 10.1172/JCI34739]
[5]   Genome-wide analysis of estrogen receptor binding sites [J].
Carroll, Jason S. ;
Meyer, Clifford A. ;
Song, Jun ;
Li, Wei ;
Geistlinger, Timothy R. ;
Eeckhoute, Jerome ;
Brodsky, Alexander S. ;
Keeton, Erika Krasnickas ;
Fertuck, Kirsten C. ;
Hall, Giles F. ;
Wang, Qianben ;
Bekiranov, Stefan ;
Sementchenko, Victor ;
Fox, Edward A. ;
Silver, Pamela A. ;
Gingeras, Thomas R. ;
Liu, X. Shirley ;
Brown, Myles .
NATURE GENETICS, 2006, 38 (11) :1289-1297
[6]   Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer [J].
Carver, Brett S. ;
Chapinski, Caren ;
Wongvipat, John ;
Hieronymus, Haley ;
Chen, Yu ;
Chandarlapaty, Sarat ;
Arora, Vivek K. ;
Le, Carl ;
Koutcher, Jason ;
Scher, Howard ;
Scardino, Peter T. ;
Rosen, Neal ;
Sawyers, Charles L. .
CANCER CELL, 2011, 19 (05) :575-586
[7]   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
[8]   An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen [J].
Doane, A. S. ;
Danso, M. ;
Lal, P. ;
Donaton, M. ;
Zhang, L. ;
Hudis, C. ;
Gerald, W. L. .
ONCOGENE, 2006, 25 (28) :3994-4008
[9]   mTORC1 Inhibition Is Required for Sensitivity to PI3K p110α Inhibitors in PIK3CA-Mutant Breast Cancer [J].
Elkabets, Moshe ;
Vora, Sadhna ;
Juric, Dejan ;
Morse, Natasha ;
Mino-Kenudson, Mari ;
Muranen, Taru ;
Tao, Jessica ;
Campos, Ana Bosch ;
Rodon, Jordi ;
Ibrahim, Yasir H. ;
Serra, Violeta ;
Rodrik-Outmezguine, Vanessa ;
Hazra, Saswati ;
Singh, Sharat ;
Kim, Phillip ;
Quadt, Cornelia ;
Liu, Manway ;
Huang, Alan ;
Rosen, Neal ;
Engelman, Jeffrey A. ;
Scaltriti, Maurizio ;
Baselga, Jose .
SCIENCE TRANSLATIONAL MEDICINE, 2013, 5 (196)
[10]   The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism [J].
Engelman, Jeffrey A. ;
Luo, Ji ;
Cantley, Lewis C. .
NATURE REVIEWS GENETICS, 2006, 7 (08) :606-619