Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer
Annunziato, S; de Ruiter, JR; Henneman, L; Brambillasca, CS; Lutz, C; Vaillant, F; Ferrante, F; Drenth, AP; van der Burg, E; Siteur, B; van Gerwen, B; de Bruijn, R; van Miltenburg, MH; Huijbers, IJ; van de Ven, M; Visvader, JE; Lindeman, GJ; Wessels, LFA; Jonkers, J
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.