Mechanisms of Therapy Resistance in Patient-Derived Xenograft Models of BRCA1-Deficient Breast Cancer
Petra ter Brugge, Petra Kristel, Eline van der Burg, Ute Boon, Michiel de Maaker, Esther Lips, Lennart Mulder, Julian de Ruiter, Catia Moutinho, Heidrun Gevensleben, Elisabetta Marangoni, Ian Majewski, Katarzyna Jozwiak, Wigard Kloosterman, Markus van Roosmalen, Karen Duran, Frans Hogervorst, Nick Turner, Manel Esteller, Edwin Cuppen Show all
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | OXFORD UNIV PRESS INC | Published : 2016
BACKGROUND: Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer. METHODS: A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined. In tumors that acquired therapy resistance, BRCA1 expression was investigated using quantitative real-time ..View full abstract
Awarded by Dutch Cancer Society
Awarded by Netherlands Organization for Scientific Research (NWO-NGI Zenith)
Awarded by Netherlands Organization for Scientific Research (NWO-ZonMW Vici)
This research was supported by grants from the Dutch Cancer Society (NKI 2011-5197 and EMCR 2014-7048); the Netherlands Organization for Scientific Research (NWO-NGI Zenith 93512009 and NWO-ZonMW Vici 91814643); the Eurocan Platform network of excellence, funded by the EU Seventh Framework Programme; the CombatCancer synergy project, funded by the European Research Council; and the Cancer Genomics Netherlands gravitation programme and Cancer Systems Biology Center (CSBC), funded by the NWO.