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53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer

التفاصيل البيبلوغرافية
العنوان: 53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer
المؤلفون: Peter Ansell, Andrea E. Wahner Hendrickson, Rutger H. T. Koornstra, Scott H. Kaufmann, Matthew W. Dudley, Jourik A. Gietema, Krista M. Goergen, X. Wei Meng, Matthew J. Maurer, Karen S. Flatten, Carla D. Van Herpen, Martha W. den Hollander, Ann L. Oberg, Rachel M. Hurley, Agnes Jager, Maja J.A. de Jonge, Maria I. Harrell, Jill M. Wagner, Elizabeth M. Swisher, Stacie Peacock Shepherd, Daniel W. Visscher, Vivian Negron
المساهمون: Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Medical Oncology
المصدر: Gynecologic Oncology, 153, 127-134
Gynecologic Oncology, 153(1), 127-134. ACADEMIC PRESS INC ELSEVIER SCIENCE
Gynecologic Oncology, 153, 1, pp. 127-134
Gynecologic Oncology, 153(1), 127-134. Academic Press
سنة النشر: 2019
مصطلحات موضوعية: 0301 basic medicine, DNA Repair, Genes, BRCA2, Genes, BRCA1, Poly (ADP-Ribose) Polymerase-1, RAD51, MULTICENTER, Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2], 0302 clinical medicine, PARP1, Medicine, Homologous Recombination, PARP inhibitors, Ovarian Neoplasms, Sulfonamides, Obstetrics and Gynecology, HR-deficiency, OPEN-LABEL, 53BP1, POLYMERASE INHIBITORS, Oncology, NIRAPARIB, 030220 oncology & carcinogenesis, Benzamides, PARP inhibitor, Female, Tumor Suppressor p53-Binding Protein 1, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], CARCINOMA, DNA repair, Poly(ADP-ribose) Polymerase Inhibitors, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Ovarian cancer, Cell Line, Tumor, Carcinoma, Humans, Clonogenic assay, REPAIR, business.industry, MUTATIONS, DNA Repair Pathway, medicine.disease, PROFICIENT, 030104 developmental biology, Drug Resistance, Neoplasm, CELLS, Cancer research, DNA damage, business, RESISTANCE
الوصف: Contains fulltext : 202591.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors have shown substantial activity in homologous recombination- (HR-) deficient ovarian cancer and are undergoing testing in other HR-deficient tumors. For reasons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Preclinical studies have demonstrated that changes in alternative DNA repair pathways affect PARP inhibitor (PARPi) sensitivity in ovarian cancer models. This has not previously been assessed in the clinical setting. METHODS: Clonogenic and plasmid-based HR repair assays were performed to compare BRCA1-mutant COV362 ovarian cancer cells with or without 53BP1 gene deletion. Archival biopsies from ovarian cancer patients in the phase I, open-label clinical trial of PARPi ABT-767 were stained for PARP1, RAD51, 53BP1 and multiple components of the nonhomologous end-joining (NHEJ) DNA repair pathway. Modified histochemistry- (H-) scores were determined for each repair protein in each sample. HRD score was determined from tumor DNA. RESULTS: 53BP1 deletion increased HR in BRCA1-mutant COV362 cells and decreased PARPi sensitivity in vitro. In 36 women with relapsed ovarian cancer, responses to the PARPi ABT-767 were observed exclusively in cancers with HR deficiency. In this subset, 7 of 18 patients (39%) had objective responses. The actual HRD score did not further correlate with change from baseline tumor volume (r=0.050; p=0.87). However, in the HR-deficient subset, decreased 53BP1 H-score was associated with decreased antitumor efficacy of ABT-767 (r=-0.69, p=0.004). CONCLUSION: Differences in complementary repair pathways, particularly 53BP1, correlate with PARPi response of HR-deficient ovarian cancers.
وصف الملف: application/pdf
تدمد: 0090-8258
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::769b957b6aeedc5c1ecaa27b29eeb2ef
http://hdl.handle.net/2066/202591
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....769b957b6aeedc5c1ecaa27b29eeb2ef
قاعدة البيانات: OpenAIRE
الوصف
تدمد:00908258