CDK4/6 inhibition presents as a therapeutic option for pediatric and adult germ cell tumors and induces cell cycle arrest and apoptosis via canonical and non-canonical mechanisms

Background: Germ cell tumors (GCTs) are the most common solid malignancies in young men. Although high cure rates at early stages can be achieved, metastases, resistance to cisplatin-based therapy, and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In this study, we analyzed the potential of CDK4/6 inhibitors palbociclib and ribociclib (PaRi) as molecular drugs to treat cisplatin-resistant and -sensitive pediatric and adult GCTs.Results: We demonstrate that adult GCTs highly express CDK4, while pediatric GCTs strongly express CDK6instead. Thus, both GCT types are potentially treatable by PaRi. GCTs presented as highly sensitive towards PaRi, which caused a decrease in viability, cell cycle arrest and apoptosis. Although GCTs mainly arrested in G1/G0 phase, some embryonal carcinoma (EC) cell lines were able to bypass the G1/S checkpoint and progressed to G2/M phase. We found that upregulation of CDK3 and downregulation of many mitosis-regulation factors, like the HAUS genes, might be responsible for bypassing the G1/S checkpoint and termination of mitosis, respectively. We postulate that GCT cells do not tolerate these alterations in the cell cycle and eventually induce apoptosis. Conclusion: Our study highlights PaRi as therapeutic options for cisplatin-resistant and -sensitive pediatric and adult GCTs.