Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Clin Pharmacol Ther. 2022 Jun;111(6):1296-1306. doi: 10.1002/cpt.2582. Epub 2022 Apr 12.
Approximately one-third of patients with metastatic castration-resistant prostate cancer (CRPC) exhibited primary abiraterone resistance. To identify alternative treatment for abiraterone nonresponders, we performed drug discovery analyses using the L1000 database using differentially expressed genes identified in tumor biopsies and patient-derived xenograft (PDX) tumors between abiraterone responders and nonresponders enrolled in PROMOTE trial. This approach identified 3 drugs, including topoisomerase II (TOP2) inhibitor mitoxantrone, CDK4/6 inhibitor palbociclib, and pan-CDK inhibitor PHA-793887. These drugs significantly suppressed the growth of abiraterone-resistant cell lines and PDX models. Moreover, we identified 11 genes targeted by all 3 drugs that were associated with worse outcomes in both the PROMOTE and Stand Up To Cancer cohorts. This 11-gene panel might also function as biomarkers to select the 3 alternative therapies for this subgroup of patients with CRPC, warranting further clinical investigation.
约三分之一的转移性去势抵抗性前列腺癌（CRPC）患者表现出原发阿比特龙耐药。为了确定阿比特龙无应答者的替代治疗方法，我们使用 L1000 数据库，对 PROMOTE 试验中阿比特龙应答者和无应答者的肿瘤活检和患者来源异种移植（PDX）肿瘤中鉴定的差异表达基因进行药物发现分析。这种方法鉴定出 3 种药物，包括拓扑异构酶 II（TOP2）抑制剂米托蒽醌、CDK4/6 抑制剂帕博西利和泛 CDK 抑制剂 PHA-793887。这些药物显著抑制了阿比特龙耐药细胞系和 PDX 模型的生长。此外，我们鉴定出这 3 种药物共同靶向的 11 个基因，它们与 PROMOTE 和 Stand Up To Cancer 队列中的不良预后相关。该 11 基因面板也可能作为生物标志物，为这部分 CRPC 患者选择这 3 种替代疗法，值得进一步临床研究。
