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, Jos Jonkers, 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, Jos Jonkers
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.
Conflict of interest statement
The authors declare no competing interests.
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References
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