Transcriptional CDK Inhibitors as Potential Treatment Option for Testicular Germ Cell Tumors.

Abstract

Simple SummaryType II testicular germ cell tumors are a severe type of cancer in young men demanding alternative treatment options to conventional chemotherapy with less side effects. In particular, patients with chemotherapy-resistant tumors face a bad prognosis and low survival rates. In other tumor entities, transcriptional cyclin-dependent kinases (7/8/9/12/13) have been demonstrated to be effective targets. Here, we studied the effects of transcriptional cyclin-dependent kinase inhibitors on a cellular and molecular level. We found several inhibitors to be highly cytotoxic for certain testicular germ cell tumor cell lines while leaving a somatic (fibroblast) control cell line unaffected. This opens up a novel field for effective and specified treatment of type II testicular germ cell tumors.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.