Elucidating acquired PARP inhibitor resistance in advanced prostate cancer.
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Authors
Seed, G
Beije, N
Yuan, W
Bertan, C
Goodall, J
Lundberg, A
Tyler, M
Figueiredo, I
Pereira, R
Baker, C
Bogdan, D
Gallagher, L
Cieslik, J-P
Greening, S
Lambros, M
Neves, R
Magraner-Pardo, L
Fowler, G
Ebbs, B
Miranda, S
Flohr, P
Bianchini, D
Rescigno, P
Porta, N
Hall, E
Gurel, B
Tunariu, N
Sharp, A
Pettit, S
Stoecklein, NH
Sandhu, S
Quigley, D
Lord, CJ
Mateo, J
Carreira, S
de Bono, J
Beije, N
Yuan, W
Bertan, C
Goodall, J
Lundberg, A
Tyler, M
Figueiredo, I
Pereira, R
Baker, C
Bogdan, D
Gallagher, L
Cieslik, J-P
Greening, S
Lambros, M
Neves, R
Magraner-Pardo, L
Fowler, G
Ebbs, B
Miranda, S
Flohr, P
Bianchini, D
Rescigno, P
Porta, N
Hall, E
Gurel, B
Tunariu, N
Sharp, A
Pettit, S
Stoecklein, NH
Sandhu, S
Quigley, D
Lord, CJ
Mateo, J
Carreira, S
de Bono, J
Document Type
Journal Article
Date
2024-12-09
Date Accepted
2024-10-28
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.
Citation
Cancer Cell, 2024,
Source Title
Cancer Cell
Publisher
CELL PRESS
ISSN
1535-6108
eISSN
1878-3686
Collections
Research Team
Cancer Biomarkers
PrCa Targeted Therapy
PrCa Targeted Therapy