Comparative analysis of the transcriptomic response to cisplatin in drug-sensitive and drug-resistant testicular germ cell tumors.

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. The global transcriptional response to acute cisplatin treatment (24 hours after a 6-hour pulse of cisplatin) was assessed in three parental embryonal carcinoma TGCT cells lines compared to multiple isogenic, stable, cisplatin-resistant clonal lines from these pa-rental cells. 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. Cisplatin resistance in TGCT cells is associated with a diminished alteration of cisplatin responsive genes especially genes known the be regulated by p53, MYC and TFRC1 that may be linked to cisplatin hypersensitivity and survival in TGCTs.