Expression and therapeutic potential of TROP2 in cisplatin-resistant germ cell tumors.

BACKGROUND AND

OBJECTIVES

Cisplatin-based chemotherapy remains the standard of care for metastatic germ cell tumors (GCTs), but patients with cisplatin-refractory disease have limited effective options and poor outcomes. There is a clear unmet need for new therapies in this setting. Antibody–drug conjugates (ADCs) have emerged as a promising class of targeted agents for chemoresistant solid tumors. This study aimed to evaluate the expression of TROP2 in cisplatin-resistant GCT metastases [MET(-R)] and to assess the cytotoxic efficacy of the anti-TROP2 ADC sacituzumab govitecan (SG) in GCT cell lines.

METHODS

TROP2 mRNA and protein expression levels were analyzed in 31 post-chemotherapy viable MET(-R) specimens, including embryonal carcinoma (EC), choriocarcinoma (CC), yolk sac tumor (YST), and teratoma (TER), using quantitative reverse transcription polymerase chain reaction and immunohistochemistry with H-score evaluation. In vitro analyses included Western blotting and cell viability assays to assess TROP2 protein expression and SG-mediated cytotoxicity in GCT cell lines.

RESULTS

TROP2 mRNA expression was significantly higher in post-chemotherapy CC- and TER-MET(-R) compared to YST-MET(-R) (p < 0.01). Immunohistochemistry showed moderate to strong membranous TROP2 expression in CC-MET(-R) [with H-score ≥ 100, median H-score 280 (interquartile range, IQR 225.0–298.0)] and TER-MET(-R) [median H-score 255 (IQR 200.0–265.0)]. Conversely, EC- and YST-MET(-R) showed absent or weak TROP2 expression [EC median H-score 22.5 (IQR 5.0–73.8); YST median H-score 0 (IQR 0–12.5)]. In vitro, SG induces dose-dependent cytotoxicity in TROP2-positive GCT cells, including cisplatin-resistant subclones (p < 0.01).

CONCLUSION

In summary, TROP2 is variably expressed in cisplatin-resistant metastatic GCTs, with high expression most often seen in CC. SG shows strong cytotoxicity in TROP2-positive, chemotherapy-resistant GCT cells; however, its clinical effectiveness still needs to be confirmed.