@article{f6a97a5ba0c44f30af8bb0653a31bdc4,
title = "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.",
author = "Lawrence, {Mitchell G.} and Porter, {Laura H.} and Nicholas Choo and David Pook and Grummet, {Jeremy P.} and Pezaro, {Carmel J.} and Shahneen Sandhu and Susanne Ramm and Jennii Luu and Andrew Bakshi and Goode, {David L.} and Elaine Sanij and Pearson, {Richard B.} and Hannan, {Ross D.} and Simpson, {Kaylene J.} and Taylor, {Renea A.} and Risbridger, {Gail P.} and Luc Furic",
note = "Funding Information: This work was supported by the National Health and Medical Research Council, Australia (fellowship to G.P. Risbridger 1102752, project grant 1138242; fellowship to R.B. Pearson 1058586 and to R.D. Hannan 116999), the Department of Health and Human Services acting through the Victorian Cancer Agency (fellowships to L. Furic MCRF16007, M.G. Lawrence MCRF18017, R.A. Taylor. MCRF15023, D.L. Goode MCRF17005, CAPTIV Program), the U.S. Department of Defense through the Prostate Cancer Research Program (G.P. Risbridger W81XWH1810349; opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense), the CASS Foundation (Medical Science grant to M.G. Lawrence 7139), Monash University Faculty of Medicine, Nursing and Health Sciences (Bridging Post-doctoral Fellowship to L.H. Porter), the Movember Foundation (Global Action Plan 1), the EJ Whitten Foundation, the Peter and Lyndy White Foundation, and TissuPath Pathology. Funding Information: We thank the patients and families who generously supported this research by consenting to provide tissue. We thank the members of the Melbourne Urological Research Alliance (MURAL), Melissa Papargiris, Jenna Kraska and Heather Madsen for providing PDXs; Kathryn Alsop, Lisa Devereux, Heather Thorne and the CASCADE rapid autopsy program; Niantao Deng and Alex Swarbrick for targeted sequencing; Wallace Crellin and James McPherson for invaluable advice; Ashlee Clark, Shivakumar Keerthikumar, Birunthi Niranjan, Michelle Richards, Linda Teng and Hong Wang for laboratory assistance; and the Monash University Histology Platform, Monash University Animal Research Laboratories, Monash Micro Imaging and the Monash Biomedicine Discovery Institute Organoid Program. This work was supported by the National Health and Medical Research Council, Australia (fellowship to G.P. Risbridger 1102752, project grant 1138242; fellowship to R.B. Pearson 1058586 and to R.D. Hannan 116999), the Department of Health and Human Services acting through the Victorian Cancer Agency (fellowships to L. Furic MCRF16007, M.G. Lawrence MCRF18017, R.A. Taylor. MCRF15023, D.L. Goode MCRF17005, CAPTIV Program), the U.S. Department of Defense through the Prostate Cancer Research Program (G.P. Risbridger W81XWH1810349; opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense), the CASS Foundation (Medical Science grant to M.G. Lawrence 7139), Monash University Faculty of Medicine, Nursing and Health Sciences (Bridging Post-doctoral Fellowship to L.H. Porter), the Movember Foundation (Global Action Plan 1), the EJ Whitten Foundation, the Peter and Lyndy White Foundation, and TissuPath Pathology. Funding Information: M.G. Lawrence reports grants from NHMRC, Victorian Cancer Agency, U.S. Department of Defense, CASS Foundation, Movember Foundation, EJ Whitten Foundation, Peter and Lydney White Foundation, and non-financial support from TissuPath Pathology during the conduct of the study; non-financial support from Astellas, Pfizer, and Zenith Epigenetics outside the submitted work; and M.G. Lawrence is an co-investigator on a Prostate Cancer Foundation/Pfizer/Senhwa funded clinical trial into combination of CX-5461 and talazoparib. L.H. Porter reports grants from NHMRC, Victorian Cancer Agency, U.S. Department of Defense, CASS Foundation, Movember Foundation, EJ Whitten Foundation, Peter and Lydney White Foundation, and non-financial support from TissuePath Pathology during the conduct of the study. N. Choo reports grants from NHMRC, Victorian Cancer Agency, U.S. Department of Defense, CASS Foundation, Movember Foundation, EJ Whitten Foundation, Peter and Lydney White Foundation, and non-financial support from TissuPath Pathology during the conduct of the study. D. Pook reports personal fees and non-financial support from Astellas and Pfizer; personal fees from Ipsen, Novartis, and Bayer; grants, personal fees, and non-financial support from Bristol-Myers Squibb; grants from Merck Sharp & Dohme, Medivation, Exelixis, and SymVivo; and grants and non-financial support from Amgen outside the submitted work. J.P. Grummet reports other support from MRI PRO PTY LTD; personal fees from BK ULTRASOUND, BIOBOT, MUNDIPHARMA, and IPSEN outside the submitted work. C.J. Pezaro reports personal fees from Astellas, AstraZeneca, Ipsen, Mundipharma, and Pfizer, and non-financial support from Janssen outside the submitted work. S. Sandhu reports grants from Novartis, AstraZeneca, Genetech, Amgen, Merck, and Merck Serono; personal fees from AstraZeneca, Amgen, Bristol Myer Squibb, and Janssen outside the submitted work. D.L. Goode reports grants from The Victorian Cancer Agency and other support from The Peter MacCallum Cancer Foundation during the conduct of the study. E. Sanij reports grants from Victorian Cancer Agency, The National Health and Medical Research Council, and Tour De Cure Foundation during the conduct of the study. R.A. Taylor reports grants from NHMRC, Victorian Cancer Agency, U.S. Department of Defense, Movember Foundation, EJ Whitten Foundation, Peter and Lyndy White Foundation; and nonfinancial support and other support from TissuPath Pathology during the conduct of the study; and reports research collaborations with Astellas, Pfizer, and Zenith Epigenetics. G.P. Risbridger reports grants from NHMRC, Victorian Cancer Agency, U.S. Department of Defense, Movember Foundation, EJ Whitten Foundation, Peter and Lyndy White Foundation, and Cass Foundation; and non-financial support from TissuPath Pathology during the conduct of the study; non-financial support from Astellas, Pfizer, and Zenith Epigenetics outside the submitted work; and G.P. Risbridger is a co-investigator on a Prostate CanFoundation/Pfizer/Senhwa funded clinical trial into combination of CX-5461 and talazoparib. L. Furic reports grants from NHMRC, PCF, and Victorian Cancer Agency, and non-financial support from Senhwa during the conduct of the study; other support from Pimera Pty Ltd outside the submitted work; and L. Furic is an co-investigator on a Prostate Cancer Foundation/Pfizer/Senhwa funded clinical trial into combination of CX-5461 and talazoparib. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research",
year = "2021",
month = nov,
doi = "10.1158/1535-7163.MCT-20-0932",
language = "English",
volume = "20",
pages = "2140--2150",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research (AACR)",
number = "11",
}
