【文献速览】-CDK7 Inhibition Potentiat

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 in- duces 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.

细胞周期依赖激酶7 (CDK7)是细胞周期和基因转录的中枢调控因子。然而，人们对其对基因组不稳定性和癌症免疫的影响知之甚少。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，在小细胞肺癌(SCLC)中诱导DNA复制应激和基因组不稳定性，同时触发免疫应答信号。这些肿瘤的内在事件激发了由T细胞引发的强大的免疫监视程序，并通过免疫检查点封锁进一步增强。将YKL-5-124与抗pd -1联合使用，在多种高度侵袭性的SCLC小鼠模型中提供了显著的生存益处，为CDK7抑制剂和免疫疗法组成的新联合方案提供了基础。