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

Autor:	Lawrence MG; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia., Porter LH; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia., Choo N; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia., Pook D; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.; Medical Oncology, Monash Health, Clayton, Victoria, Australia., Grummet JP; Epworth Healthcare, Melbourne, Victoria, Australia.; Department of Surgery, Central Clinical School, Monash University, Clayton, Victoria, Australia.; Australian Urology Associates, Melbourne, VIC, Australia., Pezaro CJ; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.; Eastern Health and Monash University Eastern Health Clinical School, Victoria, Australia.; University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom., Sandhu S; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Cancer Tissue Collection After Death (CASCADE) Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Ramm S; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Luu J; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Bakshi A; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.; Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Goode DL; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Sanij E; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia.; St Vincent's Institute, Fitzroy, VIC, Australia., Pearson RB; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia., Hannan RD; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.; ACRF Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, Australian National University, Australian Capital Territory, Australia.; School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia., Simpson KJ; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Taylor RA; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. luc.furic@petermac.org renea.taylor@monash.edu gail.risbridger@monash.edu.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Physiology, Monash University, Clayton, Victoria, Australia., Risbridger GP; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia. luc.furic@petermac.org renea.taylor@monash.edu gail.risbridger@monash.edu.; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia., Furic L; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia. luc.furic@petermac.org renea.taylor@monash.edu gail.risbridger@monash.edu.; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2021 Nov; Vol. 20 (11), pp. 2140-2150. Date of Electronic Publication: 2021 Aug 19.
DOI:	10.1158/1535-7163.MCT-20-0932
Abstrakt:	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. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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