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.
Cancer cell. 2024 Nov 14 [Epub ahead of print]
George Seed, Nick Beije, Wei Yuan, Claudia Bertan, Jane Goodall, Arian Lundberg, Matthew Tyler, Ines Figueiredo, Rita Pereira, Chloe Baker, Denisa Bogdan, Lewis Gallagher, Jan-Phillipp Cieslik, Semini Greening, Maryou Lambros, Rui Neves, Lorena Magraner-Pardo, Gemma Fowler, Berni Ebbs, Susana Miranda, Penny Flohr, Diletta Bianchini, Pasquale Rescigno, Nuria Porta, Emma Hall, Bora Gurel, Nina Tunariu, Adam Sharp, Stephen Pettit, Nikolas H Stoecklein, Shahneen Sandhu, David Quigley, Christopher J Lord, Joaquin Mateo, Suzanne Carreira, Johann de Bono
The Institute of Cancer Research, London, UK., The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK., Heinrich Heine University, Düsseldorf, Germany., The Royal Marsden NHS Foundation Trust, London, UK., UCSF, San Francisco, CA, USA., Vall d'Hebron Institute of Oncology, Barcelona, Spain., The Institute of Cancer Research, London, UK; The Royal Marsden NHS Foundation Trust, London, UK. Electronic address: .