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; Jelle Wesseling; Jos Jonkers

Journal article

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

DOI: 10.1093/jnci/djw148

Abstract

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 ..

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University of Melbourne Researchers

Ian Majewski Author Medical Biology (w.e.h.i.)

Grants

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)

Funding Acknowledgements

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.