Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer
Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer
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DOI：
10.1038/s41467-019-08301-2
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发表时间：
2019-01-23
影响因子：
16.6
通讯作者：
Jonkers, Jos
中科院分区：
文献类型：
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作者：
Annunziato, Stefano;de Ruiter, Julian R.;Jonkers, Jos
brca1突变的乳腺癌主要由含有大量候选驱动基因的DNA拷贝数改变（CNAs）驱动。这些候选的验证需要新的方法来高通量基因功能的体内扰动。在这里，我们开发了brca1缺陷乳腺癌的基因工程小鼠模型（GEMMs），通过重靶向gemm衍生的胚胎干细胞，慢病毒介导的体细胞过表达或原位CRISPR/ cas9介导的基因破坏，可以快速引入假定的驱动因素。我们使用这些方法验证Myc、Met、Pten和Rb1是brca1相关乳腺肿瘤发生的真正驱动因素。迭代小鼠模型和比较肿瘤基因组学分析表明，myc过表达强烈地重塑了brca1缺陷乳腺肿瘤的CNA格局，并确定MCL1是这些肿瘤的协同驱动因素。此外，MCL1抑制增强了PARP抑制（PARPi）的体内疗效，强调了这种联合治疗对PARPi单药反应不佳的brca1突变癌症患者的治疗潜力。
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.