The Role of TP53 in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors

Dennis M Timmerman, Thomas F Eleveld, Ad J M Gillis, Carlijn C Friedrichs, Sanne Hillenius, Tessa L Remmers, Sruthi Sriram, Leendert H J Looijenga

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Germ cell tumors (GCTs) are considered to be highly curable; however, there are major differences in the outcomes related to histology and anatomical localization. GCTs originating from the testis are, overall, sensitive to platinum-based chemotherapy, whereas GCTs originating from the mediastinum show a worse response, which remains largely unexplained. Here, we address the differences among GCTs from two different anatomical locations (testicular versus mediastinal/extragonadal), with a specific focus on the role of the P53 pathway. It was recently shown that GCTs with TP53 mutations most often localize to the mediastinum. To elucidate the underlying mechanism, TP53 knock-out lines were generated in cisplatin-sensitive and -resistant clones of the representative 2102Ep cell line (wild-type TP53 testicular GCT) and NCCIT cell line (hemizygously mutated TP53, mutant TP53 mediastinal GCT). The full knock-out of TP53 in 2102Ep and resistant NCCIT resulted in an increase in cisplatin resistance, suggesting a contributing role for P53, even in NCCIT, in which P53 had been reported to be non-functional. In conclusion, these results suggest that TP53 mutations contribute to the cisplatin-resistant phenotype of mediastinal GCTs and, therefore, are a potential candidate for targeted treatment. This knowledge provides a novel model system to elucidate the underlying mechanism of clinical behavior and possible alternative treatment of the TP53 mutant and mediastinal GCTs.

Original languageEnglish
Article number11774
JournalInternational journal of molecular sciences
Volume22
Issue number21
DOIs
Publication statusPublished - 29 Oct 2021

Keywords

  • Antineoplastic Agents/pharmacology
  • Cell Line, Tumor
  • Cisplatin/pharmacology
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic/drug effects
  • Humans
  • Male
  • Mediastinal Neoplasms/drug therapy
  • Mutation/drug effects
  • Neoplasms, Germ Cell and Embryonal/drug therapy
  • Testicular Neoplasms/drug therapy
  • Tumor Suppressor Protein p53/genetics

Fingerprint

Dive into the research topics of 'The Role of TP53 in Cisplatin Resistance in Mediastinal and Testicular Germ Cell Tumors'. Together they form a unique fingerprint.

Cite this