Journal article

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

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

MOLECULAR CANCER THERAPEUTICS | AMER ASSOC CANCER RESEARCH | Published : 2021

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 ..

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Grants

Awarded by National Health and Medical Research Council, Australia


Awarded by Department of Health and Human Services through the Victorian Cancer Agency


Awarded by U.S. Department of Defense through the Prostate Cancer Research Program


Awarded by CASS Foundation (Medical Science grant)


Funding Acknowledgements

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.The Victorian Centre for Functional Genomics (K.J. Simpson) is funded by the Australian Cancer Research Foundation (ACRF), Phenomics Australia, through funding from the Australian Government's National Collaborative Research Infrastructure Strategy (NCRIS) program and the Peter MacCallum Cancer Centre Foundation.