Abstract

BackgroundGerm cell tumours (GCTs) are the most common solid malignancies in young men. Although high cure rates 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 analysed the potential of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors palbociclib and ribociclib (PaRi) as molecular drugs to treat cisplatin-resistant and -sensitive paediatric and adult GCTs.MethodsTen GCT cell lines, including cisplatin-resistant subclones and non-malignant controls, were treated with PaRi and screened for changes in viability (triphenyl tetrazolium chloride (XTT) assay), apoptosis rates (flow cytometry, caspase assay), the cell cycle (flow cytometry), the transcriptome (RNA-sequencing, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and on protein level (western blot). Expression profiling was performed on paediatric and adult GCT tissues (expression microarrays, qRT-PCR, immunohistochemistry, ‘The Cancer Genome Atlas’ database).ResultsWe demonstrate that adult GCTs highly express CDK4, while paediatric GCTs strongly express CDK6 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 the G1/G0 phase, some embryonal carcinoma cell lines were able to bypass the G1/S checkpoint and progressed to the 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.ConclusionOur study highlights PaRi as therapeutic options for cisplatin-resistant and -sensitive paediatric and adult GCTs.

Highlights

  • Germ cell tumours (GCTs) are the most common solid malignancies in young men

  • In this study, we analysed the potential of CDK4 and CDK6 inhibitors palbociclib (PF-00080665, Pfizer Ltd.) and ribociclib (GST0000015996, Novartis Pharma AG) as therapeutic options for cisplatin-resistant and -sensitive germ cell tumours (GCTs)

  • CDK4/CDK4 was highly expressed in GCT tissues (GCNIS, seminomas, embryonal carcinomas (ECs), teratomas) and cell lines (TCam-2, seminoma; 2102EP, NCCIT, both EC; JAR, choriocarcinomas) (Fig. 1a, b)

Read more

Summary

Introduction

Germ cell tumours (GCTs) are the most common solid malignancies in young men. high cure rates 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. RESULTS: We demonstrate that adult GCTs highly express CDK4, while paediatric GCTs strongly express CDK6 instead 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. CONCLUSION: Our study highlights PaRi as therapeutic options for cisplatin-resistant and -sensitive paediatric and adult GCTs. Testicular type II germ cell tumours (GCTs), which are subdivided into seminomas and non-seminomas, arise from the precursor lesion germ cell neoplasia in situ (GCNIS), which itself is the result of a defective primordial germ cell development.[1,2,3,4]. Despite high cure rates exceeding 90% over all stages, ~10–15% of patients with advanced disease relapse despite adequate multimodal first-line and first-salvage treatments and are deemed treatment refractory.[6,7,8] Such patients are usually incurable and face an awful prognosis with a life expectancy of a few months only.[6,7,8]

Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call