SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.
SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.
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DOI：
10.1016/j.ccell.2020.04.014
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发表时间：
2020-06-08
期刊：
影响因子：
50.3
通讯作者：
Mazur PK
中科院分区：
文献类型：
--
作者：
Wang Z;Hausmann S;Lyu R;Li TM;Lofgren SM;Flores NM;Fuentes ME;Caporicci M;Yang Z;Meiners MJ;Cheek MA;Howard SA;Zhang L;Elias JE;Kim MP;Maitra A;Wang H;Bassik MC;Keogh MC;Sage J;Gozani O;Mazur PK
胰腺导管腺癌(PDAC)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抵抗MEK1/2抑制(Meki)的主要驱动因素。SETD5是由Meki耐药诱导的，它的缺失在小鼠模型和患者来源的异种移植中恢复了对Meki治疗的难治性PDAC脆弱性。SETD5缺乏组蛋白甲基转移酶活性，但支架共抑制复合体，包括HDAC3和G9a。SETD5复合体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的药物共靶向在体内维持对PDAC肿瘤生长的抑制。我们的工作揭示了SETD5是PDAC获得性Meki治疗抵抗的关键介质，并建议在临床上推广Meki的使用。在胰腺导管腺癌(PDAC)中，针对KRAS-MAPK通路的治疗的主要障碍是快速出现耐药，如MEK1/2抑制(MEKI)。Wang等人。确定由SETD5介导的临床可操作的表观遗传途径，以驱动PDAC对Meki的耐药。
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. In pancreatic ductal adenocarcinoma (PDAC), a major roadblock in therapies targeting the KRAS-MAPK pathway, such as MEK1/2 inhibition (MEKi), is the rapid emergence of resistance. Wang et al. identify a clinically actionable epigenetic pathway mediated by SETD5 to drive PDAC resistance to MEKi.
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