Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer

Stefano Annunziato, Julian R. de Ruiter, Linda Henneman, Chiara S. Brambillasca, Catrin Lutz, François Vaillant, Federica Ferrante, Anne Paulien Drenth, Eline van der Burg, Bjørn Siteur, Bas van Gerwen, Roebi de Bruijn, Martine H. van Miltenburg, Ivo J. Huijbers, Marieke van de Ven, Jane E. Visvader, Geoffrey J. Lindeman, Lodewyk F. A. Wessels () and Jos Jonkers ()
Additional contact information
Stefano Annunziato: The Netherlands Cancer Institute
Julian R. de Ruiter: The Netherlands Cancer Institute
Linda Henneman: The Netherlands Cancer Institute
Chiara S. Brambillasca: The Netherlands Cancer Institute
Catrin Lutz: The Netherlands Cancer Institute
François Vaillant: Walter and Eliza Hall Institute of Medical Research
Federica Ferrante: The Netherlands Cancer Institute
Anne Paulien Drenth: The Netherlands Cancer Institute
Eline van der Burg: The Netherlands Cancer Institute
Bjørn Siteur: The Netherlands Cancer Institute
Bas van Gerwen: The Netherlands Cancer Institute
Roebi de Bruijn: The Netherlands Cancer Institute
Martine H. van Miltenburg: The Netherlands Cancer Institute
Ivo J. Huijbers: The Netherlands Cancer Institute
Marieke van de Ven: The Netherlands Cancer Institute
Jane E. Visvader: Walter and Eliza Hall Institute of Medical Research
Geoffrey J. Lindeman: Walter and Eliza Hall Institute of Medical Research
Lodewyk F. A. Wessels: Cancer Genomics Netherlands, The Netherlands Cancer Institute
Jos Jonkers: The Netherlands Cancer Institute

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract BRCA1-mutated breast cancer is primarily driven by DNA copy-number alterations (CNAs) containing large numbers of candidate driver genes. Validation of these candidates requires novel approaches for high-throughput in vivo perturbation of gene function. Here we develop genetically engineered mouse models (GEMMs) of BRCA1-deficient breast cancer that permit rapid introduction of putative drivers by either retargeting of GEMM-derived embryonic stem cells, lentivirus-mediated somatic overexpression or in situ CRISPR/Cas9-mediated gene disruption. We use these approaches to validate Myc, Met, Pten and Rb1 as bona fide drivers in BRCA1-associated mammary tumorigenesis. Iterative mouse modeling and comparative oncogenomics analysis show that MYC-overexpression strongly reshapes the CNA landscape of BRCA1-deficient mammary tumors and identify MCL1 as a collaborating driver in these tumors. Moreover, MCL1 inhibition potentiates the in vivo efficacy of PARP inhibition (PARPi), underscoring the therapeutic potential of this combination for treatment of BRCA1-mutated cancer patients with poor response to PARPi monotherapy.

Date: 2019
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DOI: 10.1038/s41467-019-08301-2

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