Effective targeting of RNA polymerase I in treatment-resistant prostate cancer.

Abstract

BACKGROUND:

Advanced prostate cancers depend on protein synthesis for continued survival and accelerated rates of metabolism for growth. RNA polymerase I (Pol I) is the enzyme responsible for ribosomal RNA (rRNA) transcription and a rate-limiting step for ribosome biogenesis. We have shown using a specific and sensitive RNA probe for the 45S rRNA precursor that rRNA synthesis is increased in prostate adenocarcinoma compared to nonmalignant epithelium. We have introduced a first-in-class Pol I inhibitor, BMH-21, that targets cancer cells of multiple origins, and holds potential for clinical translation.

METHODS:

The effect of BMH-21 was tested in prostate cancer cell lines and in prostate cancer xenograft and mouse genetic models.

RESULTS:

We show that BMH-21 inhibits Pol I transcription in metastatic, castration-resistant, and enzalutamide treatment-resistant prostate cancer cell lines. The genetic abrogation of Pol I effectively blocks the growth of prostate cancer cells. Silencing of p53, a pathway activated downstream of Pol I, does not diminish this effect. We find that BMH-21 significantly inhibited tumor growth and reduced the Ki67 proliferation index in an enzalutamide-resistant xenograft tumor model. A decrease in 45S rRNA synthesis demonstrated on-target activity. Furthermore, the Pol I inhibitor significantly inhibited tumor growth and pathology in an aggressive genetically modified Hoxb13-MYC|Hoxb13-Cre|Ptenfl/fl (BMPC) mouse prostate cancer model.

CONCLUSION:

Taken together, BMH-21 is a novel promising molecule for the treatment of castration-resistant prostate cancer.

• Authors: Jin-Yih Low, Paul Sirajuddin, Michael Moubarek, Shreya Agarwal, Apurv Rege, Gunes Guner, Hester Liu, Zhiming Yang, Angelo M De Marzo, Charles Bieberich, Marikki Laiho
• Journal: The Prostate (Prostate) Vol. 79 Issue 16 Pg. 1837-1851 (12 2019) ISSN: 1097-0045 [Electronic] United States
• PMID: 31524299 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• BMH-21
• Benzamides
• Enzyme Inhibitors
• Heterocyclic Compounds, 4 or More Rings
• Nitriles
• RNA, Ribosomal
• Phenylthiohydantoin
• enzalutamide
• RNA Polymerase I

Topics

• Animals
• Benzamides
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Enzyme Inhibitors (pharmacology)
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Humans
• Male
• Mice
• Mice, Nude
• Molecular Targeted Therapy
• Nitriles
• PC-3 Cells
• Phenylthiohydantoin (analogs & derivatives, pharmacology)
• Prostatic Neoplasms (drug therapy, enzymology, genetics, pathology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, enzymology, genetics, pathology)
• RNA Polymerase I (antagonists & inhibitors, genetics, metabolism)
• RNA, Ribosomal (genetics)
• Random Allocation
• Transcription, Genetic (drug effects)
• Xenograft Model Antitumor Assays