Testicular Germ Cell Tumors Acquire Cisplatin Resistance by Rebalancing the Usage of DNA Repair Pathways

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Germ cell tumors (GCTs) often respond to cisplatin, but resistance develops in some patients, leading to poor prognosis.
• The molecular mechanisms driving cisplatin resistance in GCTs are not fully understood.

Purpose of the Study:

• To investigate the mechanisms of acquired cisplatin resistance in testicular germ cell tumors (TGCTs).
• To identify potential therapeutic strategies for cisplatin-refractory GCTs.

Main Methods:

• Utilized two TGCT cell lines with acquired cisplatin resistance.
• Assessed DNA repair pathways, including non-homologous end-joining (NHEJ) and homologous recombination (HR).
• Investigated the roles of TP53-binding protein 1 (53BP1) and DNA-dependent protein kinase (DNA-PKcs).
• Evaluated the efficacy of cisplatin combined with PARP inhibitors (PARPi).

Main Results:

• Cisplatin-resistant cells exhibited a non-homologous end-joining (NHEJ)-deficient phenotype with reduced 53BP1 and DNA-PKcs expression.
• Impaired NHEJ led to increased reliance on homologous recombination (HR) for DNA double-strand break (DSB) repair.
• Cisplatin-resistant cells showed resistance to PARPi monotherapy but sensitivity to cisplatin-PARPi combination therapy.
• Combination therapy demonstrated additive/synergistic effects, reducing the required cisplatin dose.

Conclusions:

• Reduced NHEJ activity is a key mechanism of acquired cisplatin resistance in GCTs.
• Targeting DNA repair pathways, specifically by combining PARPi with cisplatin, offers a promising therapeutic approach for resistant GCTs.
• Low-dose cisplatin combined with PARPi may benefit patients with cisplatin-refractory GCTs.