Genomic Activation of PPARG Reveals a Candidate Therapeutic Axis in Bladder Cancer

被引：70

作者：

Goldstein, Jonathan T. ^{[1
]}

Berger, Ashton C. ^{[1
]}

Shih, Juliann ^{[1
]}

Duke, Fujiko F. ^{[1
,6
]}

Furst, Laura ^{[1
]}

Kwiatkowski, David J. ^{[2
]}

Cherniack, Andrew D. ^{[1
,3
]}

Meyerson, Matthew ^{[1
,3
,4
,5
]}

Strathdee, Craig A. ^{[1
]}

机构：

[1] Broad Inst MIT & Harvard, Cambridge, MA USA

[2] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA USA

[3] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[4] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[5] Harvard Med Sch, Dept Pathol, Boston, MA USA

[6] Gritstone Oncol, Cambridge, MA USA

来源：

CANCER RESEARCH | 2017年 / 77卷 / 24期

关键词：

RECEPTOR-GAMMA; PIOGLITAZONE USE; URINARY-BLADDER; ACTS UPSTREAM; AGONIST; LIGAND; ALPHA; ANTAGONIST; INSULIN; BINDING;

D O I：

10.1158/0008-5472.CAN-17-1701

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The PPARG gene encoding the nuclear receptor PPARg is activated in bladder cancer, either directly by gene amplification or mutation, or indirectly by mutation of the RXRA gene, which encodes the heterodimeric partner of PPARg. Here, we show that activating alterations of PPARG or RXRA lead to a specific gene expression signature in bladder cancers. Reducing PPARG activity, whether by pharmacologic inhibition or genetic ablation, inhibited proliferation of PPARG-activated bladder cancer cells. Our results offer a preclinical proof of concept for PPARG as a candidate therapeutic target in bladder cancer. (C) 2017 AACR.

引用

页码：6987 / 6998

页数：12

共 57 条

[1] Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting [J].

Aguirre, Andrew J. ;

Meyers, Robin M. ;

Weir, Barbara A. ;

Vazquez, Francisca ;

Zhang, Cheng-Zhong ;

Ben-David, Uri ;

Cook, April ;

Ha, Gavin ;

Harrington, William F. ;

Doshi, Mihir B. ;

Kost-Alimova, Maria ;

Gill, Stanley ;

Xu, Han ;

Ali, Levi D. ;

Jiang, Guozhi ;

Pantel, Sasha ;

Lee, Yenarae ;

Goodale, Amy ;

Cherniack, Andrew D. ;

Oh, Coyin ;

Kryukov, Gregory ;

Cowley, Glenn S. ;

Garraway, Levi A. ;

Stegmaier, Kimberly ;

Roberts, Charles W. ;

Golub, Todd R. ;

Meyerson, Matthew ;

Root, David E. ;

Tsherniak, Aviad ;

Hahn, William C. .

CANCER DISCOVERY, 2016, 6 (08) :914-929

[2] PPARγ signaling and metabolism: the good, the bad and the future [J].

Ahmadian, Maryam ;

Suh, Jae Myoung ;

Hah, Nasun ;

Liddle, Christopher ;

Atkins, Annette R. ;

Downes, Michael ;

Evans, Ronald M. .

NATURE MEDICINE, 2013, 19 (05) :557-566

[3] Ligand-independent activation of peroxisome proliferator-activated receptor-γ by insulin and C-peptide in kidney proximal tubular cells -: Dependent on phosphatidylinositol 3-kinase activity [J].

Al-Rasheed, NM ;

Chana, RS ;

Baines, RJ ;

Willars, GB ;

Brunskill, NJ .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (48) :49747-49754

[4] Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study [J].

Apolo, Andrea B. ;

Infante, Jeffrey R. ;

Balmanoukian, Ani ;

Patel, Manish R. ;

Wang, Ding ;

Kelly, Karen ;

Mega, Anthony E. ;

Britten, Carolyn D. ;

Ravaud, Alain ;

Mita, Alain C. ;

Safran, Howard ;

Stinchcombe, Thomas E. ;

Srdanov, Marko ;

Gelb, Arnold B. ;

Schlichting, Michael ;

Chin, Kevin ;

Gulley, James L. .

JOURNAL OF CLINICAL ONCOLOGY, 2017, 35 (19) :2117-+

[5] The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity [J].

Barretina, Jordi ;

Caponigro, Giordano ;

Stransky, Nicolas ;

Venkatesan, Kavitha ;

Margolin, Adam A. ;

Kim, Sungjoon ;

Wilson, Christopher J. ;

Lehar, Joseph ;

Kryukov, Gregory V. ;

Sonkin, Dmitriy ;

Reddy, Anupama ;

Liu, Manway ;

Murray, Lauren ;

Berger, Michael F. ;

Monahan, John E. ;

Morais, Paula ;

Meltzer, Jodi ;

Korejwa, Adam ;

Jane-Valbuena, Judit ;

Mapa, Felipa A. ;

Thibault, Joseph ;

Bric-Furlong, Eva ;

Raman, Pichai ;

Shipway, Aaron ;

Engels, Ingo H. ;

Cheng, Jill ;

Yu, Guoying K. ;

Yu, Jianjun ;

Aspesi, Peter, Jr. ;

de Silva, Melanie ;

Jagtap, Kalpana ;

Jones, Michael D. ;

Wang, Li ;

Hatton, Charles ;

Palescandolo, Emanuele ;

Gupta, Supriya ;

Mahan, Scott ;

Sougnez, Carrie ;

Onofrio, Robert C. ;

Liefeld, Ted ;

MacConaill, Laura ;

Winckler, Wendy ;

Reich, Michael ;

Li, Nanxin ;

Mesirov, Jill P. ;

Gabriel, Stacey B. ;

Getz, Gad ;

Ardlie, Kristin ;

Chan, Vivien ;

Myer, Vic E. .

NATURE, 2012, 483 (7391) :603-607

[6] Independent Component Analysis Uncovers the Landscape of the Bladder Tumor Transcriptome and Reveals Insights into Luminal and Basal Subtypes [J].

Biton, Anne ;

Bernard-Pierrot, Isabelle ;

Lou, Yinjun ;

Krucker, Clementine ;

Chapeaublanc, Elodie ;

Rubio-Perez, Carlota ;

Lopez-Bigas, Nuria ;

Kamoun, Aurelie ;

Neuzillet, Yann ;

Gestraud, Pierre ;

Grieco, Luca ;

Rebouissou, Sandra ;

de Reynies, Aurelien ;

Benhamou, Simone ;

Lebret, Thierry ;

Southgate, Jennifer ;

Barillot, Emmanuel ;

Allory, Yves ;

Zinovyev, Andrei ;

Radvanyi, Francois .

CELL REPORTS, 2014, 9 (04) :1235-1245

[7] Near-optimal probabilistic RNA-seq quantification [J].

Bray, Nicolas L. ;

Pimentel, Harold ;

Melsted, Pall ;

Pachter, Lior .

NATURE BIOTECHNOLOGY, 2016, 34 (05) :525-527

[8] A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-γ reverses the diabetic phenotype of the Zucker diabetic fatty rat [J].

Brown, KK ;

Henke, BR ;

Blanchard, SG ;

Cobb, JE ;

Mook, R ;

Kaldor, I ;

Kliewer, SA ;

Lehmann, JM ;

Lenhard, JM ;

Harrington, WW ;

Novak, PJ ;

Faison, W ;

Binz, JG ;

Hashim, MA ;

Oliver, WO ;

Brown, HR ;

Parks, DJ ;

Plunket, KD ;

Tong, WQ ;

Menius, JA ;

Adkison, K ;

Noble, SA ;

Willson, TM .

DIABETES, 1999, 48 (07) :1415-1424

[9] The rexinoid LG100754 is a novel RXR:PPARγ agonist and decreases glucose levels in vivo [J].

Cesario, RM ;

Klausing, K ;

Razzaghi, H ;

Crombie, D ;

Rungta, D ;

Heyman, RA ;

Lala, DS .

MOLECULAR ENDOCRINOLOGY, 2001, 15 (08) :1360-1369

[10] Mechanisms of resistance in castration-resistant prostate cancer (CRPC) [J].

Chandrasekar, Thenappan ;

Yang, Joy C. ;

Gao, Allen C. ;

Evans, Christopher P. .

TRANSLATIONAL ANDROLOGY AND UROLOGY, 2015, 4 (03) :365-380

← 1 2 3 4 5 6 →