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

## TL;DR

This study compares how testicular cancer cells respond to cisplatin, finding that drug-resistant cells show weaker gene activity changes linked to survival and treatment response.

## Contribution

The study identifies specific gene pathways and regulators like p53, MYC, and TFRC1 that differ between cisplatin-sensitive and resistant testicular cancer cells.

## Key findings

- Cisplatin-sensitive cells showed stronger transcriptional responses in genes related to p53, EMT, and KRAS signaling.
- Resistant cells had reduced activity in genes regulated by p53 and MYC, including TFRC1.
- Altered gene activity in sensitive cells correlated with better survival in testicular cancer patients.

## Abstract

Testicular cancer is one of the few advanced solid tumors that can be cured with chemotherapy, specifically cisplatin-based therapy. The reasons for this, if better understood, could offer clues to better treat other more chemotherapy-refractory cancers and those rare testicular cancer patients that are resistant to cisplatin. This research uncovered differences in how cisplatin-sensitive and -resistant testicular cancer cells globally respond to cisplatin transcriptionally that may explain and contribute to our understanding of testicular cancer curability and acquired cisplatin resistance.

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.