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

<b>Background: </b>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.<b>Results:</b> We demonstrate that adult GCTs<i> </i>highly express <i>CDK4</i>, while pediatric GCTs strongly express <i>CDK6</i>instead. 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 <i>CDK3</i> and downregulation of many mitosis-regulation factors, like the <i>HAUS</i> 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. <b>Conclusion:</b> Our study highlights PaRi as therapeutic options for cisplatin-resistant and -sensitive pediatric and adult GCTs.