Elucidating acquired PARP inhibitor resistance in advanced prostate cancer

George Seed(Institute of Cancer Research), Nick Beije(Royal Marsden NHS Foundation Trust), Wei Yuan(Institute of Cancer Research), Cláudia Bertan(Institute of Cancer Research), Jane Goodall(Institute of Cancer Research), Arian Lundberg(Institute of Cancer Research), Matthew A. Tyler(Institute of Cancer Research), Ines Figueiredo(Institute of Cancer Research), Rita Pereira(Institute of Cancer Research), Chloe Baker(Institute of Cancer Research), Denisa Bogdan(Institute of Cancer Research), Lewis Gallagher(Institute of Cancer Research), Jan-Phillipp Cieslik(Heinrich Heine University Düsseldorf), Semini Greening(Institute of Cancer Research), Maryou Lambros(Institute of Cancer Research), Rui Neves(Heinrich Heine University Düsseldorf), Lorena Magraner-Pardo(Institute of Cancer Research), Gemma Fowler(Institute of Cancer Research), Berni Ebbs(Institute of Cancer Research), Susana Miranda(Institute of Cancer Research), Penny Flohr(Institute of Cancer Research), Diletta Bianchini(Royal Marsden NHS Foundation Trust), Pasquale Rescigno(Institute of Cancer Research), Núria Porta(Institute of Cancer Research), Emma Hall(Institute of Cancer Research), Bora Gürel(Institute of Cancer Research), Nina Tunariu(Royal Marsden NHS Foundation Trust), Adam Sharp(Royal Marsden NHS Foundation Trust), Stephen Pettit(Institute of Cancer Research), Nikolas H. Stoecklein(Heinrich Heine University Düsseldorf), Shahneen Sandhu(Royal Marsden NHS Foundation Trust), David A. Quigley, Christopher J. Lord(Institute of Cancer Research), Joaquı́n Mateo(Vall d'Hebron Institute of Oncology), Suzanne Carreira(Institute of Cancer Research), Johann S. de Bono(Royal Marsden NHS Foundation Trust)
Cancer Cell
November 21, 2024
10.1016/j.ccell.2024.10.015
Cited by 32Open Access
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Abstract

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.

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