Sistema de Salut de Catalunya
Institut Català de la Salut
[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
Vall d'Hebron Barcelona Hospital Campus
2025-01-17T11:57:28Z
2025-01-17T11:57:28Z
2024-12-09
DNA repair; Genomics; Prostate cancer
Reparació de l'ADN; Genòmica; Càncer de pròstata
Reparación del ADN; Genómica; Cáncer de próstata
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.
Article
Published version
English
Pròstata - Càncer - Tractament; Enzims - Inhibidors - Ús terapèutic; Resistència als medicaments; Anomalies cromosòmiques; DISEASES::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms::Prostatic Neoplasms, Castration-Resistant; Other subheadings::Other subheadings::Other subheadings::/drug therapy; CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Poly(ADP-ribose) Polymerase Inhibitors; Other subheadings::Other subheadings::/therapeutic use; PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm; PHENOMENA AND PROCESSES::Genetic Phenomena::Genetic Variation::Mutation; ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata::neoplasias prostáticas resistentes a la castración; Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia; COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de poli(ADP-ribosa) polimerasas; Otros calificadores::Otros calificadores::/uso terapéutico; FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos; FENÓMENOS Y PROCESOS::fenómenos genéticos::variación genética::mutación
Elsevier
Cancer Cell;42(12)
https://doi.org/10.1016/j.ccell.2024.10.015
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
