Constitutively-active androgen receptor variants function independently of the HSP90 chaperone but do not confer resistance to HSP90 inhibitors.
Constitutively-active androgen receptor variants function independently of the HSP90 chaperone but do not confer resistance to HSP90 inhibitors.
复制标题
DOI：
10.18632/oncotarget.975
复制
发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
Butler LM
中科院分区：
文献类型：
--
作者：
Gillis JL;Selth LA;Centenera MM;Townley SL;Sun S;Plymate SR;Tilley WD;Butler LM
致死性去势抵抗性前列腺癌的发生与雄激素受体（AR）的适应性变化相关，包括突变型受体和截短的组成型活性AR变体的出现。AR依赖于分子伴侣HSP 90在正常和恶性前列腺细胞中的功能，但在AR表达异常的环境中对HSP 90的需求在很大程度上是未知的。在这里，我们研究了三种HSP 90抑制剂17-AAG、HSP 990和AUY 922对临床相关AR错义突变体和截短变体的疗效。HSP 90抑制有效抑制了野生型AR和所有测试的AR错义突变体的信号传导。相比之下，两种截短的AR变体AR-V7和ARv 567 es表现出对HSP 90抑制剂的显著抗性。支持这一观察结果，截短的AR变体的核定位不受HSP 90抑制的影响，并且在前列腺癌细胞中不能检测到AR变体：HSP 90复合物。有趣的是，HSP 90抑制导致AR-V7和ARv 567 es在细胞系和人肿瘤外植体中积累。尽管AR变体明显独立于HSP 90及其治疗相关诱导，但具有AR-V7或ARv 567 es内源性或强制表达的细胞系的生长仍然对AUY 922高度敏感。这项研究表明，功能性AR变体信号传导不会对HSP 90抑制产生抗性，从而深入了解AR和HSP 90之间的相互作用，并为HSP 90抑制剂在晚期前列腺癌中的临床应用提供了进一步的动力。
The development of lethal, castration resistant prostate cancer is associated with adaptive changes to the androgen receptor (AR), including the emergence of mutant receptors and truncated, constitutively active AR variants. AR relies on the molecular chaperone HSP90 for its function in both normal and malignant prostate cells, but the requirement for HSP90 in environments with aberrant AR expression is largely unknown. Here, we investigated the efficacy of three HSP90 inhibitors, 17-AAG, HSP990 and AUY922, against clinically-relevant AR missense mutants and truncated variants. HSP90 inhibition effectively suppressed the signaling of wild-type AR and all AR missense mutants tested. By contrast, two truncated AR variants, AR-V7 and ARv567es, exhibited marked resistance to HSP90 inhibitors. Supporting this observation, nuclear localization of the truncated AR variants was not affected by HSP90 inhibition and AR variant:HSP90 complexes could not be detected in prostate cancer cells. Interestingly, HSP90 inhibition resulted in accumulation of AR-V7 and ARv567es in both cell lines and human tumor explants. Despite the apparent independence of AR variants from HSP90 and their treatment-associated induction, the growth of cell lines with endogenous or enforced expression of AR-V7 or ARv567es remained highly sensitive to AUY922. This study demonstrates that functional AR variant signaling does not confer resistance to HSP90 inhibition, yields insight into the interaction between AR and HSP90 and provides further impetus for the clinical application of HSP90 inhibitors in advanced prostate cancer.
登录
查看更多内容
影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
3
作者：
Iyer, Gopa;Morris, Michael J.;Rathkopf, Dana;Slovin, Susan F.;Steers, Macaulay;Larson, Steven M.;Schwartz, Lawrence H.;Curley, Tracy;DeLaCruz, Anthony;Ye, Qing;Heller, Glenn;Egorin, Merrill J.;Ivy, S. Percy;Rosen, Neal;Scher, Howard I.;Solit, David B.
通讯作者：
Solit, David B.
影响因子：
3.9
作者：
Dehm SM;Tindall DJ
通讯作者：
Tindall DJ
影响因子：
--
作者：
Buchanan, G;Yang, MO;Tilley, WD
通讯作者：
Tilley, WD
影响因子：
50.3
作者：
Cai C;He HH;Chen S;Coleman I;Wang H;Fang Z;Chen S;Nelson PS;Liu XS;Brown M;Balk SP
通讯作者：
Balk SP