Funke Kai, Düster Robert, Wilson Prince De-Graft, Arévalo Lena, Geyer Matthias, Schorle Hubert
Department of Developmental Pathology, Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany.
The Institute of Structural Biology, University of Bonn, 53127 Bonn, Germany.
Cancers (Basel). 2022 Mar 26;14(7):1690. doi: 10.3390/cancers14071690.
Type II testicular germ cell tumors (TGCT) are the most frequently diagnosed solid malignancy in young men. Up to 15% of patients with metastatic non-seminomas show cisplatin resistance and a very poor survival rate due to lacking treatment options. Transcriptional cyclin-dependent kinases (CDK) have been shown to be effective targets in the treatment of different types of cancer. Here, we investigated the effects of the CDK inhibitors dinaciclib, flavopiridol, YKL-5-124, THZ1, NVP2, SY0351 and THZ531. An XTT viability assay revealed a strong cytotoxic impact of CDK7/12/13 inhibitor SY0351 and CDK9 inhibitor NVP2 on the TGCT wild-type cell lines (2102EP, NCCIT, TCam2) and the cisplatin-resistant cell lines (2102EP-R, NCCIT-R). The CDK7 inhibitor YKL-5-124 showed a strong impact on 2102EP, 2102EP-R, NCCIT and NCCIT-R cell lines, leaving the MPAF control cell line mostly unaffected. FACS-based analysis revealed mild effects on the cell cycle of 2102EP and TCam2 cells after SY0351, YKL-5-124 or NVP2 treatment. Molecular analysis showed a cell-line-specific response for SY0351 and NVP2 inhibition while YKL-5-124 induced similar molecular changes in 2102EP, TCam2 and MPAF cells. Thus, after TGCT subtype determination, CDK inhibitors might be a potential alternative for optimized and individualized therapy independent of chemotherapy sensitivity.
II型睾丸生殖细胞肿瘤（TGCT）是年轻男性中最常被诊断出的实体恶性肿瘤。高达15%的转移性非精原细胞瘤患者表现出顺铂耐药，且由于缺乏治疗选择，生存率极低。转录细胞周期蛋白依赖性激酶（CDK）已被证明是治疗不同类型癌症的有效靶点。在此，我们研究了CDK抑制剂dinaciclib、flavopiridol、YKL-5-124、THZ1、NVP2、SY0351和THZ531的作用。XTT活力测定显示，CDK7/12/13抑制剂SY0351和CDK9抑制剂NVP2对TGCT野生型细胞系（2102EP、NCCIT、TCam2）和顺铂耐药细胞系（2102EP-R、NCCIT-R）具有强烈的细胞毒性作用。CDK7抑制剂YKL-5-124对2102EP、2102EP-R、NCCIT和NCCIT-R细胞系有强烈影响，而MPAF对照细胞系基本不受影响。基于流式细胞术的分析显示，SY0351、YKL-5-124或NVP2处理后，对2102EP和TCam2细胞的细胞周期有轻微影响。分子分析显示，SY0351和NVP2抑制呈现细胞系特异性反应，而YKL-5-124在2102EP、TCam2和MPAF细胞中诱导了相似的分子变化。因此，在确定TGCT亚型后，CDK抑制剂可能是一种潜在的替代方案，可用于优化和个体化治疗，而不受化疗敏感性的影响。
