A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer

被引：129

作者：

Lunardi, Andrea ^{[1
]}

Ala, Ugo ^{[1
,2
]}

Epping, Mirjam T. ^{[1
]}

Salmena, Leonardo ^{[1
,3
,4
]}

Clohessy, John G. ^{[1
,3
,4
]}

Webster, Kaitlyn A. ^{[1
]}

Wang, Guocan ^{[1
,3
,4
,5
]}

Mazzucchelli, Roberta ^{[6
]}

Bianconi, Maristella ^{[7
]}

Stack, Edward C. ^{[8
,9
,10
]}

Lis, Rosina ^{[8
,9
]}

Patnaik, Akash ^{[11
]}

Cantley, Lewis C. ^{[12
,13
]}

Bubley, Glenn ^{[11
]}

Cordon-Cardo, Carlos ^{[14
]}

Gerald, William L. ^{[4
]}

Montironi, Rodolfo ^{[6
]}

Signoretti, Sabina ^{[9
,10
]}

Loda, Massimo ^{[8
,9
,15
]}

Nardella, Caterina ^{[1
,3
,4
,16
]}

Pandolfi, Pier Paolo ^{[1
,3
,4
]}

机构：

[1] Harvard Univ, Beth Israel Deaconess Med Ctr, Beth Israel Deaconess Canc Ctr, Canc Genet Program,Dept Med & Pathol,Med Sch, Boston, MA 02215 USA

[2] Univ Turin, Ctr Mol Biotechnol, Dept Genet Biol & Biochem, Turin, Italy

[3] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Canc Biol & Genet Program, New York, NY 10021 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Pathol, Human Oncol & Pathogenesis Program, New York, NY 10021 USA

[5] Cornell Univ, Weill Grad Sch Med Sci, Biochem Cell & Mol Biol Program, New York, NY 10021 USA

[6] Polytech Univ Marche Reg Ancona, United Hosp, Inst Pathol Anat & Histopathol, Ancona, Italy

[7] Polytech Univ Marche Reg Ancona, United Hosp, Postgrad Sch Med Oncol, Clin Oncol, Ancona, Italy

[8] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[10] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA

[11] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Hematol Oncol, Boston, MA 02215 USA

[12] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA

[13] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA

[14] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA

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

[16] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Preclin Murine Pharmacogenet Facil, Boston, MA 02215 USA

来源：

NATURE GENETICS | 2013年 / 45卷 / 07期

基金：

美国国家卫生研究院;

关键词：

GENE-EXPRESSION ANALYSIS; PANCREATIC-CANCER; APOPTOSIS; PROGRESSION; XAF1; TARGET; CELLS; P53; DUTASTERIDE; SIGNATURES;

D O I：

10.1038/ng.2650

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten loss-driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed with deletion of either Trp53 or Zbtb7a together with Pten, leading to the development of castration-resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1, XIAP and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments.

引用

页码：747 / +

页数：11

共 49 条

[1] Characterizing the Contribution of Stem/Progenitor Cells to Tumorigenesis in the Pten-/- TP53-/- Prostate Cancer Model [J].

Abou-Kheir, Wassim G. ;

Hynes, Paul G. ;

Martin, Philip L. ;

Pierce, Rachel ;

Kelly, Kathleen .

STEM CELLS, 2010, 28 (12) :2129-2140

[2] Proliferation- and apoptosis-associated factors in advanced prostatic carcinomas before and after androgen deprivation therapy:: prognostic significance of p21/WAF1/CIP1 expression [J].

Baretton, GB ;

Klenk, U ;

Diebold, J ;

Schmeller, N ;

Löhrs, U .

BRITISH JOURNAL OF CANCER, 1999, 80 (3-4) :546-555

[3] 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

[4]

CATALONA WJ, 1994, NEW ENGL J MED, V331, P996

[5] Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer [J].

Chang, Kai-Hsiung ;

Li, Rui ;

Papari-Zareei, Mahboubeh ;

Watumull, Lori ;

Zhao, Yan Daniel ;

Auchus, Richard J. ;

Sharifi, Nima .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (33) :13728-13733

[6] Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis [J].

Chen, ZB ;

Trotman, LC ;

Shaffer, D ;

Lin, HK ;

Dotan, ZA ;

Niki, M ;

Koutcher, JA ;

Scher, HI ;

Ludwig, T ;

Gerald, W ;

Cordon-Cardo, C ;

Pandolfi, PP .

NATURE, 2005, 436 (7051) :725-730

[7] A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response [J].

Chen, Zhao ;

Cheng, Katherine ;

Walton, Zandra ;

Wang, Yuchuan ;

Ebi, Hiromichi ;

Shimamura, Takeshi ;

Liu, Yan ;

Tupper, Tanya ;

Ouyang, Jing ;

Li, Jie ;

Gao, Peng ;

Woo, Michele S. ;

Xu, Chunxiao ;

Yanagita, Masahiko ;

Altabef, Abigail ;

Wang, Shumei ;

Lee, Charles ;

Nakada, Yuji ;

Pena, Christopher G. ;

Sun, Yanping ;

Franchetti, Yoko ;

Yao, Catherine ;

Saur, Amy ;

Cameron, Michael D. ;

Nishino, Mizuki ;

Hayes, D. Neil ;

Wilkerson, Matthew D. ;

Roberts, Patrick J. ;

Lee, Carrie B. ;

Bardeesy, Nabeel ;

Butaney, Mohit ;

Chirieac, Lucian R. ;

Costa, Daniel B. ;

Jackman, David ;

Sharpless, Norman E. ;

Castrillon, Diego H. ;

Demetri, George D. ;

Jaenne, Pasi A. ;

Pandolfi, Pier Paolo ;

Cantley, Lewis C. ;

Kung, Andrew L. ;

Engelman, Jeffrey A. ;

Wong, Kwok-Kin .

NATURE, 2012, 483 (7391) :613-617

[8]

Dai Y, 2011, AM J CANCER RES, V1, P128

[9] Adenovirus-mediated down-regulation of X-linked inhibitor of apoptosis protein inhibits colon cancer [J].

Dai, Yun ;

Qiao, Liang ;

Chan, Kwok Wah ;

Yang, Mo ;

Ye, Jieyu ;

Zhang, Rongxin ;

Ma, Juan ;

Zou, Bing ;

Lam, Colin S. C. ;

Wang, Jide ;

Pang, Roberta ;

Tan, Victoria P. Y. ;

Lan, H. Y. ;

Wong, Benjamin C. Y. .

MOLECULAR CANCER THERAPEUTICS, 2009, 8 (09) :2762-2770

[10] Combination Therapy of Antiandrogen and XIAP Inhibitor for Treating Advanced Prostate Cancer [J].

Danquah, Michael ;

Duke, Charles B., III ;

Patil, Renukadevi ;

Miller, Duane D. ;

Mahato, Ram I. .

PHARMACEUTICAL RESEARCH, 2012, 29 (08) :2079-2091

← 1 2 3 4 5 →