Comparative Analysis of the Transcriptomic Response to Cisplatin in Drug-Sensitive and Drug-Resistant Testicular Germ Cell Tumors.

Background/Objectives: Testicular germ cell tumors (TGCTs) are uniquely curable with cisplatin-based therapies even when widely metastatic; however, cisplatin resistance does occur, resulting in very poor prognosis. The mechanisms to explain TGCT hypersensitivity to cisplatin and mechanisms of resistance are not well-understood. Methods: The global transcriptional response to acute cisplatin treatment (24 h after a 6 h pulse of cisplatin) was assessed in three parental embryonal carcinoma TGCT cells lines compared to multiple isogenic, stable, cisplatin-resistant clonal lines from these parental cells. Results: Cisplatin treatment of parental cells consistently showed a more robust overall transcriptional response to cisplatin compared to their cisplatin-resistant cellular counterparts for a common set of genes and pathways including the upregulation of genes associated with histone modifications and p53, EMT, and KRAS signaling and the downregulation of genes normally upregulated by MYC. Focusing on genes exclusively altered in parental cells revealed upregulated genes known to be induced by p53 and downregulated by MYC and the transferrin receptor, TFRC1. Several of these p53/MYC/TFRC1 targets were associated with a higher instance of disease-free survival in a cohort of TGCT patients. Conclusions: Cisplatin resistance in TGCT cells is associated with a diminished alteration in cisplatin-responsive genes, especially genes known to be regulated by p53, MYC and TFRC1, that may be linked to cisplatin hypersensitivity and survival in TGCTs.