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 c...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Cancer cell 2024-12, Vol.42 (12), p.2113-2123.e4
Hauptverfasser:	Seed, George, Beije, Nick, Yuan, Wei, Bertan, Claudia, Goodall, Jane, Lundberg, Arian, Tyler, Matthew, Figueiredo, Ines, Pereira, Rita, Baker, Chloe, Bogdan, Denisa, Gallagher, Lewis, Cieslik, Jan-Phillipp, Greening, Semini, Lambros, Maryou, Neves, Rui, Magraner-Pardo, Lorena, Fowler, Gemma, Ebbs, Berni, Miranda, Susana, Flohr, Penny, Bianchini, Diletta, Rescigno, Pasquale, Porta, Nuria, Hall, Emma, Gurel, Bora, Tunariu, Nina, Sharp, Adam, Pettit, Stephen, Stoecklein, Nikolas H., Sandhu, Shahneen, Quigley, David, Lord, Christopher J., Mateo, Joaquin, Carreira, Suzanne, de Bono, Johann
Format:	Artikel
Sprache:	eng
Schlagworte:	BRCA2 Protein - genetics cfDNA DNA repair Drug Resistance, Neoplasm - genetics genomics Humans Male Mutation PARP inhibition Phthalazines - pharmacology Phthalazines - therapeutic use Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use prostate cancer Prostatic Neoplasms, Castration-Resistant - drug therapy Prostatic Neoplasms, Castration-Resistant - genetics Prostatic Neoplasms, Castration-Resistant - pathology reversion
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	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
ISSN:	1535-6108 1878-3686 1878-3686
DOI:	10.1016/j.ccell.2024.10.015