SETD5 协调的染色质重编程调节靶向性胰腺癌治疗的适应性耐药。
SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.
机构信息
Department of Biology, Stanford University, Stanford, CA 94305, USA.
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
出版信息
Cancer Cell. 2020 Jun 8;37(6):834-849.e13. doi: 10.1016/j.ccell.2020.04.014. Epub 2020 May 21.
Abstract
Molecular mechanisms underlying adaptive targeted therapy resistance in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistance and its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse models and patient-derived xenografts. SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5 complex regulates known drug resistance pathways to reprogram cellular responses to MEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growth inhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance in PDAC and suggests a context for advancing MEKi use in the clinic.
摘要
胰腺癌（PDAC）中适应性靶向治疗耐药的分子机制尚不清楚。在这里，我们发现 SETD5 是 PDAC 对 MEK1/2 抑制（MEKi）耐药的主要驱动因素。SETD5 被 MEKi 耐药诱导，其缺失恢复了难治性 PDAC 对 MEKi 治疗的敏感性，在小鼠模型和患者来源的异种移植物中均如此。SETD5 缺乏组蛋白甲基转移酶活性，但支架一个共抑制复合物，包括 HDAC3 和 G9a。SETD5 复合物的基因沉默调节已知的耐药途径，以重新编程对 MEKi 的细胞反应。MEK1/2、HDAC3 和 G9a 的药理学联合靶向治疗在体内持续抑制 PDAC 肿瘤生长。我们的工作揭示了 SETD5 是 PDAC 获得性 MEKi 治疗耐药的关键介质，并为在临床上推进 MEKi 的使用提供了一个背景。
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