A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 9; pp. 2207 - 2212
• Main Authors: Kurmis, Alexis A., Yang, Fei, Welch, Timothy R., Nickols, Nicholas G., Dervan, Peter B.
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 01.05.2017
• Subjects: Androgen receptors; Androgens; Animals; Antagonists; Antifungal agents; Antitumor activity; Cell Line, Tumor; Deoxyribonucleic acid; DNA; Drug Resistance, Neoplasm - drug effects; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genomic analysis; Glucocorticoids; Humans; Imidazole; Imidazoles - administration & dosage; Male; Mice; Nylons - pharmacology; Phenylthiohydantoin - administration & dosage; Phenylthiohydantoin - analogs & derivatives; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Pyrroles - administration & dosage; Receptors, Androgen - drug effects; Receptors, Glucocorticoid - antagonists & inhibitors; Ribonucleic acid; RNA; Toxicity; Transcription; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-2503

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. Cancer Res; 77(9); 2207–12. ©2017 AACR.