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CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer.
Cancer Cell ( IF 48.8 ) Pub Date : 2019-12-26 , DOI: 10.1016/j.ccell.2019.11.003 Hua Zhang 1 , Camilla L Christensen 2 , Ruben Dries 3 , Matthew G Oser 2 , Jiehui Deng 1 , Brian Diskin 4 , Fei Li 1 , Yuanwang Pan 1 , Xuzhu Zhang 5 , Yandong Yin 5 , Eleni Papadopoulos 1 , Val Pyon 1 , Cassandra Thakurdin 1 , Nicholas Kwiatkowski 6 , Kandarp Jani 2 , Alexandra R Rabin 1 , Dayanne M Castro 7 , Ting Chen 1 , Heather Silver 1 , Qingyuan Huang 1 , Mirna Bulatovic 1 , Catríona M Dowling 1 , Belen Sundberg 4 , Alan Leggett 6 , Michela Ranieri 1 , Han Han 1 , Shuai Li 1 , Annan Yang 2 , Kristen E Labbe 1 , Christina Almonte 1 , Vladislav O Sviderskiy 8 , Max Quinn 1 , Jack Donaghue 1 , Eric S Wang 6 , Tinghu Zhang 6 , Zhixiang He 6 , Vamsidhar Velcheti 1 , Peter S Hammerman 2 , Gordon J Freeman 9 , Richard Bonneau 7 , William G Kaelin 10 , Kate D Sutherland 11 , Ariena Kersbergen 12 , Andrew J Aguirre 13 , Guo-Cheng Yuan 3 , Eli Rothenberg 5 , George Miller 4 , Nathanael S Gray 14 , Kwok-Kin Wong 1
Cancer Cell ( IF 48.8 ) Pub Date : 2019-12-26 , DOI: 10.1016/j.ccell.2019.11.003 Hua Zhang 1 , Camilla L Christensen 2 , Ruben Dries 3 , Matthew G Oser 2 , Jiehui Deng 1 , Brian Diskin 4 , Fei Li 1 , Yuanwang Pan 1 , Xuzhu Zhang 5 , Yandong Yin 5 , Eleni Papadopoulos 1 , Val Pyon 1 , Cassandra Thakurdin 1 , Nicholas Kwiatkowski 6 , Kandarp Jani 2 , Alexandra R Rabin 1 , Dayanne M Castro 7 , Ting Chen 1 , Heather Silver 1 , Qingyuan Huang 1 , Mirna Bulatovic 1 , Catríona M Dowling 1 , Belen Sundberg 4 , Alan Leggett 6 , Michela Ranieri 1 , Han Han 1 , Shuai Li 1 , Annan Yang 2 , Kristen E Labbe 1 , Christina Almonte 1 , Vladislav O Sviderskiy 8 , Max Quinn 1 , Jack Donaghue 1 , Eric S Wang 6 , Tinghu Zhang 6 , Zhixiang He 6 , Vamsidhar Velcheti 1 , Peter S Hammerman 2 , Gordon J Freeman 9 , Richard Bonneau 7 , William G Kaelin 10 , Kate D Sutherland 11 , Ariena Kersbergen 12 , Andrew J Aguirre 13 , Guo-Cheng Yuan 3 , Eli Rothenberg 5 , George Miller 4 , Nathanael S Gray 14 , Kwok-Kin Wong 1
Affiliation
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Cyclin-dependent kinase 7 (CDK7) is a central regulator of the cell cycle and gene transcription. However, little is known about its impact on genomic instability and cancer immunity. Using a selective CDK7 inhibitor, YKL-5-124, we demonstrated that CDK7 inhibition predominately disrupts cell-cycle progression and induces DNA replication stress and genome instability in small cell lung cancer (SCLC) while simultaneously triggering immune-response signaling. These tumor-intrinsic events provoke a robust immune surveillance program elicited by T cells, which is further enhanced by the addition of immune-checkpoint blockade. Combining YKL-5-124 with anti-PD-1 offers significant survival benefit in multiple highly aggressive murine models of SCLC, providing a rationale for new combination regimens consisting of CDK7 inhibitors and immunotherapies.
中文翻译：
CDK7抑制增强了基因组的不稳定性，从而触发了小细胞肺癌的抗肿瘤免疫力。
细胞周期蛋白依赖性激酶7（CDK7）是细胞周期和基因转录的中央调节器。然而，对其基因组不稳定性和癌症免疫力的影响知之甚少。使用选择性CDK7抑制剂YKL-5-124，我们证明CDK7抑制主要破坏细胞周期进程，并诱导DNA复制压力和小细胞肺癌（SCLC）中的基因组不稳定性，同时触发免疫应答信号传导。这些肿瘤内在事件激发了由T细胞引发的强大的免疫监视程序，通过添加免疫检查点封锁进一步增强了免疫监视程序。YKL-5-124与抗PD-1的结合在SCLC的多种高度侵袭性小鼠模型中提供了显着的生存优势，为由CDK7抑制剂和免疫疗法组成的新联合治疗方案提供了理论依据。
更新日期：2019-12-27
中文翻译：
CDK7抑制增强了基因组的不稳定性，从而触发了小细胞肺癌的抗肿瘤免疫力。
细胞周期蛋白依赖性激酶7（CDK7）是细胞周期和基因转录的中央调节器。然而，对其基因组不稳定性和癌症免疫力的影响知之甚少。使用选择性CDK7抑制剂YKL-5-124，我们证明CDK7抑制主要破坏细胞周期进程，并诱导DNA复制压力和小细胞肺癌（SCLC）中的基因组不稳定性，同时触发免疫应答信号传导。这些肿瘤内在事件激发了由T细胞引发的强大的免疫监视程序，通过添加免疫检查点封锁进一步增强了免疫监视程序。YKL-5-124与抗PD-1的结合在SCLC的多种高度侵袭性小鼠模型中提供了显着的生存优势，为由CDK7抑制剂和免疫疗法组成的新联合治疗方案提供了理论依据。
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