SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.,Cancer Cell

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SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.
Cancer Cell ( IF 48.8 ) Pub Date : 2020-05-21 , DOI: 10.1016/j.ccell.2020.04.014
Zhentian Wang ₁ , Simone Hausmann ₂ , Ruitu Lyu ₃ , Tie-Mei Li ₁ , Shane M Lofgren ₂ , Natasha M Flores ₂ , Mary E Fuentes ₂ , Marcello Caporicci ₂ , Ze Yang ₁ , Matthew Joseph Meiners ₄ , Marcus Adrian Cheek ₄ , Sarah Ann Howard ₄ , Lichao Zhang ₅ , Joshua Eric Elias ₅ , Michael P Kim ₆ , Anirban Maitra ₇ , Huamin Wang ₈ , Michael Cory Bassik ₉ , Michael-Christopher Keogh ₄ , Julien Sage ₁₀ , Or Gozani ₁ , Pawel K Mazur ₂

Affiliation

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.
Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA.
EpiCypher Inc., Durham, NC 27709, USA.
Chan Zuckenberg Biohub, Stanford, CA 94305, USA.
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.

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.

中文翻译：

SETD5 协调的染色质重编程调节对靶向胰腺癌治疗的适应性抵抗。

对胰腺导管腺癌 (PDAC) 中适应性靶向治疗耐药的分子机制知之甚少。在这里，我们将 SETD5 确定为 PDAC 对 MEK1/2 抑制 (MEKi) 的抗性的主要驱动因素。SETD5 由 MEKi 抗性诱导，其缺失恢复了小鼠模型和患者来源的异种移植物对 MEKi 治疗的难治性 PDAC 易感性。SETD5 缺乏组蛋白甲基转移酶活性，但支持共阻遏复合物，包括 HDAC3 和 G9a。SETD5 复合物的基因沉默调节已知的耐药途径，以重新编程细胞对 MEKi 的反应。MEK1/2、HDAC3 和 G9a 的药理学共同靶向在体内维持 PDAC 肿瘤生长抑制. 我们的工作揭示了 SETD5 作为 PDAC 中获得性 MEKi 治疗抗性的关键介质，并为推进 MEKi 在临床中的使用提供了背景。

更新日期：2020-05-21

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