Acquired resistance to the second-generation androgen receptor antagonist enzalutamide in castration-resistant prostate cancer.
Acquired resistance to the second-generation androgen receptor antagonist enzalutamide in castration-resistant prostate cancer.
复制标题
DOI：
10.18632/oncotarget.8456
复制
发表时间：
2016-05-03
期刊：
影响因子：
--
通讯作者：
Vander Griend DJ
中科院分区：
文献类型：
--
作者：
Kregel S;Chen JL;Tom W;Krishnan V;Kach J;Brechka H;Fessenden TB;Isikbay M;Paner GP;Szmulewitz RZ;Vander Griend DJ
Enzalutamide （MDV3100）是第二代雄激素受体（AR）拮抗剂，在治疗去势抵抗性前列腺癌（CRPC）方面已被证实有效。然而，大多数接受治疗的患者会产生耐药性和疾病进展，因此迫切需要确定介导耐药性的新的靶向途径。本研究的目的是开发和广泛表征一系列对恩杂鲁胺耐药的前列腺癌细胞系。通过在恩杂鲁胺中长期培养（bbb6个月），使四种遗传上不同的ar阳性和ar通路依赖的前列腺癌细胞（cwrr - r1, LAPC-4, LNCaP, VCaP）对恩杂鲁胺产生耐药性。这些品系的广泛表征记录了不同的体外生长特性和AR通路调节。耐enzalutamide的LNCaP和CWR-R1细胞，而不是LAPC-4和VCAP细胞，在体内表现出更高的去势抵抗和转移性生长。短期enzalutamide处理与enzalutamide耐药细胞之间的全局基因表达分析发现，在获得enzalutamide耐药后，AR途径和非AR途径相关的变化都得到了恢复。进一步的分析显示，四种耐药细胞系之间很少有共同的基因表达变化。因此，虽然ar介导的途径在一定程度上促进了恩杂鲁胺的耐药，但对几种细胞系的无偏倚方法表明，通过多效性、非ar介导的机制，对耐药有更大的贡献。
Enzalutamide (MDV3100) is a second generation Androgen Receptor (AR) antagonist with proven efficacy in the treatment of castration resistant prostate cancer (CRPC). The majority of treated patients, however, develop resistance and disease progression and there is a critical need to identify novel targetable pathways mediating resistance. The purpose of this study was to develop and extensively characterize a series of enzalutamide-resistant prostate cancer cell lines. Four genetically distinct AR-positive and AR-pathway dependent prostate cancer cell lines (CWR-R1, LAPC-4, LNCaP, VCaP) were made resistant to enzalutamide by long-term culture (> 6 months) in enzalutamide. Extensive characterization of these lines documented divergent in vitro growth characteristics and AR pathway modulation. Enzalutamide-resistant LNCaP and CWR-R1 cells, but not LAPC-4 and VCAP cells, demonstrated increased castration-resistant and metastatic growth in vivo. Global gene expression analyses between short-term enzalutamide treated vs. enzalutamide-resistant cells identified both AR pathway and non-AR pathway associated changes that were restored upon acquisition of enzalutamide resistance. Further analyses revealed very few common gene expression changes between the four resistant cell lines. Thus, while AR-mediated pathways contribute in part to enzalutamide resistance, an unbiased approach across several cell lines demonstrates a greater contribution toward resistance via pleiotropic, non-AR mediated mechanisms.
登录
查看更多内容
影响因子：
7.7
作者：
Balbas MD;Evans MJ;Hosfield DJ;Wongvipat J;Arora VK;Watson PA;Chen Y;Greene GL;Shen Y;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
28.2
作者：
Korpal, Manav;Korn, Joshua M.;Zhu, Ping
通讯作者：
Zhu, Ping
影响因子：
3.9
作者：
Dehm SM;Tindall DJ
通讯作者：
Tindall DJ
影响因子：
3
作者：
Isikbay M;Otto K;Kregel S;Kach J;Cai Y;Vander Griend DJ;Conzen SD;Szmulewitz RZ
通讯作者：
Szmulewitz RZ
DOI：
10.1056/nejmoa1315815
发表时间：
2014-09-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
通讯作者：
Luo J