Kurmis Alexis A, Yang Fei, Welch Timothy R, Nickols Nicholas G, Dervan Peter B
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California.
Department of Radiation Oncology, David Geffen School of Medicine at UCLA, VA Greater Los Angeles Healthcare System, Los Angeles, California.
Cancer Res. 2017 May 1;77(9):2207-2212. doi: 10.1158/0008-5472.CAN-16-2503. Epub 2017 Mar 30.
The LREX' prostate cancer model is resistant to the antiandrogen enzalutamide via activation of an alternative nuclear hormone receptor, glucocorticoid receptor (GR), which has similar DNA-binding specificity to the androgen receptor (AR). Small molecules that target DNA to interfere with protein-DNA interactions may retain activity against enzalutamide-resistant prostate cancers where ligand-binding domain antagonists are ineffective. We reported previously that a pyrrole-imidazole (Py-Im) polyamide designed to bind the consensus androgen response element half-site has antitumor activity against hormone-sensitive prostate cancer. In enzalutamide-resistant LREX' cells, Py-Im polyamide interfered with both AR- and GR-driven gene expression, whereas enzalutamide interfered with only that of AR. Genomic analyses indicated immediate interference with the AR transcriptional pathway. Long-term treatment with Py-Im polyamide demonstrated a global decrease in RNA levels consistent with inhibition of transcription. The polyamide was active against two enzalutamide-resistant xenografts with minimal toxicity. Overall, our results identify Py-Im polyamide as a promising therapeutic strategy in enzalutamide-resistant prostate cancer. .
LREX前列腺癌模型通过激活一种替代性核激素受体——糖皮质激素受体（GR），对抗雄激素恩杂鲁胺产生抗性，该受体与雄激素受体（AR）具有相似的DNA结合特异性。靶向DNA以干扰蛋白质-DNA相互作用的小分子可能对配体结合域拮抗剂无效的恩杂鲁胺抗性前列腺癌保持活性。我们之前报道过，一种设计用于结合共有雄激素反应元件半位点的吡咯-咪唑（Py-Im）聚酰胺对激素敏感性前列腺癌具有抗肿瘤活性。在恩杂鲁胺抗性LREX细胞中，Py-Im聚酰胺干扰了AR和GR驱动的基因表达，而恩杂鲁胺仅干扰了AR驱动的基因表达。基因组分析表明对AR转录途径有即时干扰。用Py-Im聚酰胺进行长期治疗显示RNA水平总体下降，这与转录抑制一致。该聚酰胺对两种恩杂鲁胺抗性异种移植瘤具有活性，且毒性极小。总体而言，我们的结果表明Py-Im聚酰胺是恩杂鲁胺抗性前列腺癌一种有前景的治疗策略。
