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

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 identifiy 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.

BRCA1突变型乳腺癌主要由携带大量候选驱动基因的DNA拷贝数变异（copy-number alterations, CNAs）驱动。对上述候选驱动基因的验证，亟需可实现高通量体内基因功能扰动的新型实验策略。本研究构建了BRCA1缺陷型乳腺癌的基因工程小鼠模型（genetically engineered mouse models, GEMMs），可通过三种途径快速引入推定驱动基因：对GEMM来源的胚胎干细胞进行靶向重编辑、慢病毒介导的体细胞过表达，或原位CRISPR/Cas9介导的基因敲除。我们利用上述模型与方法，验证了Myc、Met、Pten及Rb1可作为BRCA1相关乳腺肿瘤发生的确凿驱动基因。迭代小鼠建模与比较肿瘤基因组学分析表明，MYC过表达可显著重塑BRCA1缺陷型乳腺肿瘤的CNA特征谱，并鉴定出MCL1为此类肿瘤的协同驱动基因。此外，MCL1抑制剂可增强PARP抑制剂（PARP inhibition, PARPi）的体内抗肿瘤效力，凸显了该联合疗法对于PARPi单药治疗应答不佳的BRCA1突变型癌症患者的治疗潜力。