耐药性导致表观遗传靶向治疗产生与增强子重塑相关的肿瘤细胞脆弱性。
Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling.
机构信息
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Bioinformatics Graduate Program, Boston University, Boston, MA 02215, USA.
出版信息
Cancer Cell. 2018 Dec 10;34(6):922-938.e7. doi: 10.1016/j.ccell.2018.11.005.
Drug resistance represents a major challenge to achieving durable responses to cancer therapeutics. Resistance mechanisms to epigenetically targeted drugs remain largely unexplored. We used bromodomain and extra-terminal domain (BET) inhibition in neuroblastoma as a prototype to model resistance to chromatin modulatory therapeutics. Genome-scale, pooled lentiviral open reading frame (ORF) and CRISPR knockout rescue screens nominated the phosphatidylinositol 3-kinase (PI3K) pathway as promoting resistance to BET inhibition. Transcriptomic and chromatin profiling of resistant cells revealed that global enhancer remodeling is associated with upregulation of receptor tyrosine kinases (RTKs), activation of PI3K signaling, and vulnerability to RTK/PI3K inhibition. Large-scale combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations. These studies provide a roadmap to elucidate resistance to epigenetic-targeted therapeutics and inform efficacious combination therapies.
耐药性是实现癌症治疗持久反应的主要挑战。针对表观遗传靶向药物的耐药机制在很大程度上仍未得到探索。我们使用神经母细胞瘤中的溴结构域和末端结构域（BET）抑制作为模型来模拟对染色质调节治疗药物的耐药性。基于全基因组的、 pooled 的慢病毒开放阅读框（ORF）和 CRISPR 敲除挽救筛选将磷脂酰肌醇 3-激酶（PI3K）途径鉴定为促进 BET 抑制耐药性的途径。耐药细胞的转录组学和染色质分析表明，全局增强子重塑与受体酪氨酸激酶（RTKs）的上调、PI3K 信号的激活以及对 RTK/PI3K 抑制的易感性有关。BET 抑制剂的大规模组合筛选发现，PI3K 抑制剂是最具协同作用的一线组合之一。这些研究为阐明针对表观遗传靶向治疗药物的耐药性提供了路线图，并为有效的联合治疗提供了信息。
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