A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer.
A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer.
复制标题
DOI：
10.1038/ng.2650
复制
发表时间：
2013-07
期刊：
影响因子：
30.8
通讯作者：
Pandolfi, Pier Paolo
中科院分区：
文献类型：
--
作者：
Lunardi, Andrea;Ala, Ugo;Epping, Mirjam T.;Salmena, Leonardo;Clohessy, John G.;Webster, Kaitlyn A.;Wang, Guocan;Mazzucchelli, Roberta;Bianconi, Maristella;Stack, Edward C.;Lis, Rosina;Patnaik, Akash;Cantley, Lewis C.;Bubley, Glenn;Cordon-Cardo, Carlos;Gerald, William L.;Montironi, Rodolfo;Signoretti, Sabina;Loda, Massimo;Nardella, Caterina;Pandolfi, Pier Paolo
在此，我们报告了一项综合分析，该分析利用前列腺癌基因小鼠模型的治疗数据以及患者的临床数据来阐明去势抵抗的新机制。我们发现，在 Pten 缺失驱动的前列腺癌小鼠模型中，去势通过诱导细胞凋亡和增殖阻断来抵消肿瘤进展。相反，当 Trp53 或 Lrf 与 Pten 一起缺失时，这种反应就会被绕过，导致去势抵抗性前列腺癌 (CRPC) 的发展。从机制上讲，对小鼠模型和患者数据的综合采集将 XAF1-XIAP/SRD5A1 的表达模式识别为 CRPC 的预测性和可操作的特征。重要的是，我们表明联合抑制 XIAP、SRD5A1 和 AR 途径可以克服去势抵抗。因此，我们的联合临床方法有助于对患者进行分层，并开发量身定制的创新治疗方法。
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 upon deletion of either Trp53 or Lrf 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/SRD5A1 as a predictive and actionable signature for CRPC. Importantly, we show that combined inhibition of XIAP, SRD5A1, and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates stratification of patients and the development of tailored and innovative therapeutic treatments.
登录
查看更多内容
影响因子：
64.8
作者：
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
通讯作者：
Wong, Kwok-Kin
影响因子：
2
作者：
Nastiuk KL;Liu H;Hamamura M;Muftuler LT;Nalcioglu O;Krolewski JJ
通讯作者：
Krolewski JJ
影响因子：
5.7
作者：
Huang, Jia;Yao, Wei-yan;Yuan, Yao-zong
通讯作者：
Yuan, Yao-zong
影响因子：
8.8
作者：
Baretton, GB;Klenk, U;Löhrs, U
通讯作者：
Löhrs, U
影响因子：
11.8
作者：
Maeda, Takahiro;Ito, Keisuke;Merghoub, Taha;Poliseno, Laura;Hobbs, Robin M.;Wang, Guocan;Dong, Lin;Maeda, Manarni;Dore, Louis C.;Zelent, Arthur;Luzzatto, Lucio;Teruya-Feldstein, Julie;Weiss, Mitchell J.;Pandolfi, Pier Paolo
通讯作者：
Pandolfi, Pier Paolo