dc.contributor
Institut Català de la Salut
dc.contributor
[Seed G, Yuan W, Bertan C, Goodall J, Lundberg A] The Institute of Cancer Research, London, UK. [Beije N] The Institute of Cancer Research, London, UK. The Royal Marsden NHS Foundation Trust, London, UK. [Mateo J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
dc.contributor
Vall d'Hebron Barcelona Hospital Campus
dc.contributor.author
Seed, George
dc.contributor.author
Beije, Nick
dc.contributor.author
Yuan, Wei
dc.contributor.author
Bertan, Claudia
dc.contributor.author
Goodall, Jane
dc.contributor.author
Lundberg, Arian
dc.contributor.author
Mateo, Joaquin
dc.date.accessioned
2025-10-24T09:34:16Z
dc.date.available
2025-10-24T09:34:16Z
dc.date.issued
2025-01-17T11:57:28Z
dc.date.issued
2025-01-17T11:57:28Z
dc.date.issued
2024-12-09
dc.identifier
Seed G, Beije N, Yuan W, Bertan C, Goodall J, Lundberg A, et al. Elucidating acquired PARP inhibitor resistance in advanced prostate cancer. Cancer Cell. 2024 Dec 9;42(12):2113-2123.e4.
dc.identifier
https://hdl.handle.net/11351/12431
dc.identifier
10.1016/j.ccell.2024.10.015
dc.identifier
001363388800001
dc.identifier.uri
http://hdl.handle.net/11351/12431
dc.description.abstract
DNA repair; Genomics; Prostate cancer
dc.description.abstract
Reparació de l'ADN; Genòmica; Càncer de pròstata
dc.description.abstract
Reparación del ADN; Genómica; Cáncer de próstata
dc.description.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.
dc.format
application/pdf
dc.relation
Cancer Cell;42(12)
dc.relation
https://doi.org/10.1016/j.ccell.2024.10.015
dc.rights
Attribution 4.0 International
dc.rights
http://creativecommons.org/licenses/by/4.0/
dc.rights
info:eu-repo/semantics/openAccess
dc.subject
Pròstata - Càncer - Tractament
dc.subject
Enzims - Inhibidors - Ús terapèutic
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Resistència als medicaments
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Anomalies cromosòmiques
dc.subject
DISEASES::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms::Prostatic Neoplasms, Castration-Resistant
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Other subheadings::Other subheadings::Other subheadings::/drug therapy
dc.subject
CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Poly(ADP-ribose) Polymerase Inhibitors
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Other subheadings::Other subheadings::/therapeutic use
dc.subject
PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm
dc.subject
PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation
dc.subject
ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata::neoplasias prostáticas resistentes a la castración
dc.subject
Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia
dc.subject
COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de poli(ADP-ribosa) polimerasas
dc.subject
Otros calificadores::Otros calificadores::/uso terapéutico
dc.subject
FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos
dc.subject
FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación
dc.title
Elucidating acquired PARP inhibitor resistance in advanced prostate cancer
dc.type
info:eu-repo/semantics/article
dc.type
info:eu-repo/semantics/publishedVersion
