Chen Eddy J, Sowalsky Adam G, Gao Shuai, Cai Changmeng, Voznesensky Olga, Schaefer Rachel, Loda Massimo, True Lawrence D, Ye Huihui, Troncoso Patricia, Lis Rosina L, Kantoff Philip W, Montgomery Robert B, Nelson Peter S, Bubley Glenn J, Balk Steven P, Taplin Mary-Ellen
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Clin Cancer Res. 2015 Mar 15;21(6):1273-80. doi: 10.1158/1078-0432.CCR-14-1220. Epub 2014 Oct 15.
The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (AR) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone-activated mutant ARs.
AR was examined by targeted sequencing in metastatic tumor biopsies from 18 patients with CRPC who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole-exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone.
The progesterone-activated T878A-mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant-treated patient, but not in a second clonally related resistant focus that instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of patients with CRPC treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wild-type AR.
These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition.
细胞色素P450 17A1（CYP17A1）抑制剂阿比特龙可显著降低雄激素前体水平，因此对去势抵抗性前列腺癌（CRPC）有效。然而，阿比特龙会使孕酮水平升高，而孕酮可激活先前在氟他胺耐药肿瘤中鉴定出的某些突变雄激素受体（AR）。因此，我们试图确定CYP17A1抑制剂治疗是否会筛选出孕酮激活的突变AR。
对18例接受CYP17A1抑制剂（17例接受阿比特龙，1例接受酮康唑）单药治疗或联合度他雄胺治疗且病情进展的CRPC患者的转移瘤活检组织进行靶向测序，检测AR情况，并对1例接受新辅助亮丙瑞林加阿比特龙治疗患者的残留肿瘤进行全外显子组测序。
在18例CRPC病例中的3例中，孕酮激活的T878A突变AR以高等位基因频率存在。在新辅助治疗患者的一个耐药肿瘤灶中也存在该突变，但在另一个克隆相关的耐药灶中不存在，后者丢失了一个PTEN拷贝和两个CHD1拷贝。T878A突变在接受阿比特龙加度他雄胺治疗的CRPC患者亚组中似乎不太常见，转染研究表明，与野生型AR相比，度他雄胺是T878A更有效的直接拮抗剂。
这些发现表明，筛选出表达孕酮激活的突变AR的肿瘤细胞是对CYP17A1抑制产生耐药的一种机制。
