美国德克萨斯大学MD安德森癌症中心Pawel K. Mazur和斯坦福大学Or Gozani研究组合作发现，SETD5协同染色质重编程可调控针对胰腺癌靶向治疗的适应性耐药。相关论文于2020年6月8日发表在《癌细胞》杂志上。

研究人员发现SETD5是胰腺导管腺癌（PDAC）耐受MEK1 / 2抑制（MEKi）的主要原因。SETD5是由MEKi耐药性诱导产生的；在小鼠模型和患者来源的异种移植物中，SETD5缺失可恢复难治性PDAC对MEKi治疗的敏感性。SETD5缺乏组蛋白甲基转移酶活性，但支持包括HDAC3和G9a在内的共阻遏复合物。

对SETD5复合物的基因沉默可调节已知的耐药性途径以重新对MEKi的细胞应答。针对MEK1 / 2、HDAC3和G9a靶点的药物抑制在体内维持了对PDAC肿瘤生长的抑制作用。该研究发现SETD5是PDAC中获得性MEKi抗药性的关键介体，并为在临床上促进MEKi使用提供了指导。

附：英文原文

Title: SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy

Author: Zhentian Wang, Simone Hausmann, Ruitu Lyu, Tie-Mei Li, Shane M. Lofgren, Natasha M. Flores, Mary E. Fuentes, Marcello Caporicci, Ze Yang, Matthew Joseph Meiners, Marcus Adrian Cheek, Sarah Ann Howard, Lichao Zhang, Joshua Eric Elias, Michael P. Kim, Anirban Maitra, Huamin Wang, Michael Cory Bassik, Michael-Christopher Keogh, Julien Sage, Or Gozani, Pawel K. Mazur

Issue&Volume: 2020/06/08

Abstract: Molecular mechanisms underlying adaptive targeted therapy resistance in pancreaticductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a majordriver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistanceand its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse modelsand patient-derived xenografts. SETD5 lacks histone methyltransferase activity butscaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5complex regulates known drug resistance pathways to reprogram cellular responses toMEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growthinhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance inPDAC and suggests a context for advancing MEKi use in the clinic.

DOI: 10.1016/j.ccell.2020.04.014

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30213-0