CX-5461 Sensitizes DNA Damage Repair-proficient Castrate-resistant Prostate Cancer to PARP Inhibition.

Abstract

Monotherapy with PARP inhibitors is effective for the subset of castrate-resistant prostate cancer (CRPC) with defects in homologous recombination (HR) DNA repair. New treatments are required for the remaining tumors, and an emerging strategy is to combine PARP inhibitors with other therapies that induce DNA damage. Here we tested whether PARP inhibitors are effective for HR-proficient CRPC, including androgen receptor (AR)-null tumors, when used in combination with CX-5461, a small molecule that inhibits RNA polymerase I transcription and activates the DNA damage response, and has antitumor activity in early phase I trials. The combination of CX-5461 and talazoparib significantly decreased in vivo growth of patient-derived xenografts of HR-proficient CRPC, including AR-positive, AR-null, and neuroendocrine tumors. CX-5461 and talazoparib synergistically inhibited the growth of organoids and cell lines, and significantly increased the levels of DNA damage. Decreased tumor growth after combination therapy was maintained for 2 weeks without treatment, significantly increasing host survival. Therefore, combination treatment with CX-5461 and talazoparib is effective for HR-proficient tumors that are not suitable for monotherapy with PARP inhibitors, including AR-null CRPC. This expands the spectrum of CRPC that is sensitive to PARP inhibition.

• Authors: Mitchell G Lawrence, Laura H Porter, Nicholas Choo, David Pook, Jeremy P Grummet, Carmel J Pezaro, Shahneen Sandhu, Susanne Ramm, Jennii Luu, Andrew Bakshi, David L Goode, Elaine Sanij, Richard B Pearson, Ross D Hannan, Kaylene J Simpson, Renea A Taylor, Gail P Risbridger, Luc Furic
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 20 Issue 11 Pg. 2140-2150 (11 2021) ISSN: 1538-8514 [Electronic] United States
• PMID: 34413130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Benzothiazoles
• CX 5461
• Naphthyridines
• Poly(ADP-ribose) Polymerase Inhibitors

Topics

• Animals
• Benzothiazoles (pharmacology, therapeutic use)
• DNA Damage (genetics)
• Humans
• Male
• Mice
• Naphthyridines (pharmacology, therapeutic use)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology, therapeutic use)
• Prostatic Neoplasms (drug therapy)