THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors.
THZ1 targeting CDK7 suppresses STAT transcriptional activity and sensitizes T-cell lymphomas to BCL2 inhibitors.
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DOI：
10.1038/ncomms14290
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发表时间：
2017-01-30
影响因子：
16.6
通讯作者：
Cerchietti L
中科院分区：
文献类型：
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作者：
Cayrol F;Praditsuktavorn P;Fernando TM;Kwiatkowski N;Marullo R;Calvo-Vidal MN;Phillip J;Pera B;Yang SN;Takpradit K;Roman L;Gaudiano M;Crescenzo R;Ruan J;Inghirami G;Zhang T;Cremaschi G;Gray NS;Cerchietti L
外周t细胞淋巴瘤（PTCL）是一种侵袭性疾病，对化疗反应差，生存率低。迫切需要确定针对PTCL生物学的有效策略。在这里，我们报道PTCL对转录靶向药物敏感，特别是对THZ1敏感，THZ1是细胞周期蛋白依赖性激酶7 （CDK7）的共价抑制剂。即使在携带激活STAT3突变Y640F的PTCL细胞中，stat信号通路也极易受到THZ1的影响。在突变细胞中，CDK7抑制降低了STAT3染色质结合和高度转录靶基因如MYC、PIM1、MCL1、CD30、IL2RA、CDC25A和IL4R的表达。在存活细胞中，THZ1降低stat调控的抗凋亡BH3家族成员MCL1和BCL-XL的表达，使PTCL细胞对BH3模拟药物敏感。因此，THZ1和BH3模拟obatoclax的结合改善了原发性PTCL离体培养和两个stat3突变PTCL异种移植物的淋巴瘤生长控制，为这些患者描绘了一种潜在的靶向药物治疗选择。t细胞淋巴瘤是一种预后不良的侵袭性疾病。在这里，作者表明THZ1，一种CDK7抑制剂，抑制STAT转录活性，导致t细胞淋巴瘤细胞凋亡和对BCL2抑制剂的敏感性。
Peripheral T-cell lymphomas (PTCL) are aggressive diseases with poor response to chemotherapy and dismal survival. Identification of effective strategies to target PTCL biology represents an urgent need. Here we report that PTCL are sensitive to transcription-targeting drugs, and, in particular, to THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7). The STAT-signalling pathway is highly vulnerable to THZ1 even in PTCL cells that carry the activating STAT3 mutation Y640F. In mutant cells, CDK7 inhibition decreases STAT3 chromatin binding and expression of highly transcribed target genes like MYC, PIM1, MCL1, CD30, IL2RA, CDC25A and IL4R. In surviving cells, THZ1 decreases the expression of STAT-regulated anti-apoptotic BH3 family members MCL1 and BCL-XL sensitizing PTCL cells to BH3 mimetic drugs. Accordingly, the combination of THZ1 and the BH3 mimetic obatoclax improves lymphoma growth control in a primary PTCL ex vivo culture and in two STAT3-mutant PTCL xenografts, delineating a potential targeted agent-based therapeutic option for these patients. T-cell lymphomas are aggressive diseases associated with poor outcome. Here, the authors show that the THZ1, a CDK7 inhibitor, suppresses STAT transcriptional activity leading to apoptosis and sensitization to BCL2 inhibitors in T-cell lymphomas.