Elucidating acquired PARP inhibitor resistance in advanced prostate cancer
PARP inhibition (PARPi) has anti-tumor activity against castration-resistant prostate cancer (CRPC) with homologous recombination repair (HRR) defects. However, mechanisms underlying PARPi resistance are not fully understood. While acquired mutations restoring BRCA genes are well documented, their clinical relevance, frequency, and mechanism of generation remain unclear. Moreover, how resistance emerges in BRCA2 homozygously deleted (HomDel) CRPC is unknown. Evaluating samples from patients with metastatic CRPC treated in the TOPARP-B trial, we identify reversion mutations in most BRCA2/PALB2-mutated tumors (79%) by end of treatment. Among reversions mediated by frameshift deletions, 60% are flanked by DNA microhomologies, implicating POLQ-mediated repair. The number of reversions and time of their detection associate with radiological progression-free survival and overall survival (p < 0.01). For BRCA2 HomDels, selection for rare subclones without BRCA2-HomDel is observed following PARPi, confirmed by single circulating-tumor-cell genomics, biopsy fluorescence in situ hybridization (FISH), and RNAish. These data support the need for restored HRR function in PARPi resistance.
Authors
- Cláudia Bertan (ORCID: https://orcid.org/0000-0003-4211-0649)
- George Seed (ORCID: https://orcid.org/0000-0002-1105-1781)
- Matthew A. Tyler (ORCID: https://orcid.org/0000-0001-5433-7870)
- Pasquale Rescigno (ORCID: https://orcid.org/0000-0002-4668-4765)
- Bora Gürel (ORCID: https://orcid.org/0000-0002-5018-8078)
- Arian Lundberg (ORCID: https://orcid.org/0000-0002-6630-2787)
- Joaquı́n Mateo (ORCID: https://orcid.org/0000-0001-5336-2548)
- Nick Beije (ORCID: https://orcid.org/0000-0001-5462-9486)
- Berni Ebbs
- David A. Quigley (ORCID: https://orcid.org/0000-0002-4726-1473)
- Nikolas Hendrik Stoecklein (ORCID: https://orcid.org/0000-0002-3412-594X)
- Denisa Bogdan (ORCID: https://orcid.org/0000-0002-3017-4832)
- Nina Tunariu (ORCID: https://orcid.org/0000-0001-6656-3699)
- Emma Hall (ORCID: https://orcid.org/0000-0001-5999-5020)
- Gemma Fowler
- Susana Miranda (ORCID: https://orcid.org/0000-0002-5936-2706)
- Shahneen Kaur Sandhu (ORCID: https://orcid.org/0000-0002-8660-4475)
- Lewis Gallagher (ORCID: https://orcid.org/0000-0003-2694-3157)
- Penny Flohr (ORCID: https://orcid.org/0000-0001-9908-0474)
- Chloe Baker
- Adam Sharp (ORCID: https://orcid.org/0000-0002-3740-1612)
- Johann Sebastian De Bono (ORCID: https://orcid.org/0000-0002-2034-595X)
- Rui Neves
- Núria Porta (ORCID: https://orcid.org/0000-0003-2458-2167)
- Stephen Pettit (ORCID: https://orcid.org/0000-0001-5241-8431)
- Suzanne Carreira (ORCID: https://orcid.org/0000-0002-5077-5379)
- Christopher J. Lord (ORCID: https://orcid.org/0000-0002-3226-0515)
- Diletta Bianchini (ORCID: https://orcid.org/0009-0002-5071-7301)
- Lorena Magraner-Pardo (ORCID: https://orcid.org/0000-0002-9064-4330)
- Rita Pereira (ORCID: https://orcid.org/0000-0002-3834-3709)
- Wei Yuan (ORCID: https://orcid.org/0000-0001-9171-0267)
- Ines Figueiredo (ORCID: https://orcid.org/0009-0007-7334-7362)
- Jane Goodall
- Maryou Lambros
- Semini Greening
- Jan-Phillipp Cieslik
Institutions
- Royal Marsden NHS Foundation Trust (GB)
- Institute of Cancer Research (GB)
- Vall d'Hebron Institute of Oncology (ES)
- Heinrich Heine University Düsseldorf (DE)
Publication Details
- Journal
- Cancer Cell
- Published
- 2024-11-21
- DOI
- https://doi.org/10.1016/j.ccell.2024.10.015
- Citations
- 26
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 7.35
Funders
- U.S. Department of Defense
- Prostate Cancer Foundation
- V Foundation for Cancer Research
- AstraZeneca
- Movember Foundation
- Royal Marsden NHS Foundation Trust
- Cancer Research UK
- National Institute for Health and Care Research
- Prostate Cancer UK
- Medical Research Council