Renal cell carcinoma (RCC) is a major cancer of the kidney. The 5-year survival rate is overall 74% and only 8% for Stage 4 cancers. Several agents including tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint inhibitors are available as first- or second-line therapy for metastatic RCC. However, the survival benefits are limited. Recently, THZ1 has been identified as a cyclin-dependent kinase 7 (CDK7) inhibitor that interferes with the transcriptional machinery. Although it is apparently effective in various cancer models, the data for RCC has never been reported. In this study, we demonstrated the impact of CDK7 expression on tumor progression and patient survival in a clinical cohort. We found that THZ1 induced apoptosis and cell cycle arrest in RCC cells, thereby reducing cell viability. Furthermore, THZ1 acted synergistically with temsirolimus in vitro, probably by inhibiting autophagy. Moreover, compared to either THZ1 or temsirolimus used individually, the combination treatment further suppressed tumor growth in vivo. These results indicate that CDK7 is associated with the progression and prognosis of RCC, and is a potential therapeutic target for overcoming drug resistance in this cancer.

中文翻译：

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共价CDK7抑制剂THZ1通过抑制人肾细胞癌中的自噬而增强西罗莫司诱导的细胞毒性。

肾细胞癌（RCC）是肾脏的主要癌症。总体而言，其5年生存率是74％，而4期癌症的生存率仅为8％。包括酪氨酸激酶抑制剂，mTOR抑制剂和免疫检查点抑制剂在内的几种药物可用作转移性RCC的一线或二线治疗。但是，生存利益是有限的。最近，THZ1被确定为干扰转录机制的细胞周期蛋白依赖性激酶7（CDK7）抑制剂。尽管它在各种癌症模型中显然有效，但从未报道过RCC的数据。在这项研究中，我们证明了CDK7表达在临床队列中对肿瘤进展和患者生存的影响。我们发现THZ1诱导RCC细胞凋亡和细胞周期停滞，从而降低细胞活力。此外，THZ1在体外与西罗莫司起协同作用，可能是通过抑制自噬。此外，与单独使用的THZ1或西罗莫司相比，联合治疗可进一步抑制体内肿瘤的生长。这些结果表明CDK7与RCC的进展和预后相关，并且是克服该癌症中的耐药性的潜在治疗靶标。