GCT-27

Hyperactivation of the Fanconi Anemia Pathway Mediates Acquired Cisplatin Resistance in a Subset of Testicular Germ Cell Tumor Cells

Testicular germ cell tumors (TGCTs) are highly curable with cisplatin, yet ~20% of patients relapse or become refractory, with mechanisms of resistance remaining poorly understood. Using paired cisplatin-sensitive (cis-s) and -resistant (cis-r) TGCT cell lines, Caggiano et al. investigated the role of the Fanconi anemia (FA) DNA repair pathway in mediating acquired resistance.

In GCT27cis-r cells, cisplatin exposure induced hyperactivation of the FA pathway compared to GCT27cis-s cells. Western blotting revealed increased basal FANCD2 expression and a greater fraction of monoubiquitinated FANCD2 (Ub-FANCD2) following drug treatment (Fig. 1E). Immunofluorescence confirmed a significantly higher number of nuclear FANCD2 foci in S-phase GCT27cis-r cells both during and after cisplatin exposure (Fig. 1F, G). This hyperactivation correlated with enhanced chromatin loading, as shown by increased Ub-FANCD2 in the chromatin-bound fraction (Fig. 1H).

In contrast, the 2102EPcis-r model did not exhibit FA pathway hyperactivation. Despite increased basal FANCD2 expression (Fig. 2F), 2102EPcis-r cells showed no elevation in FANCD2 foci formation (Fig. 2E) or ubiquitination levels (Fig. 2G) compared to 2102EPcis-s cells. These findings demonstrate that hyperactivation of the FA repair pathway mediates cisplatin resistance in a subset of TGCT cells, highlighting mechanistic heterogeneity across resistant models.