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Background and Objectives <p>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.</p> Methods <p>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.</p> Results <p><i>TROP2</i> mRNA expression was significantly higher in post-chemotherapy CC- and TER-MET(-R) compared to YST-MET(-R) (<i>p</i> &lt; 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 (<i>p</i> &lt; 0.01).</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月7日

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  • Laurenz Sperber,
  • Melanie von Brandenstein,
  • Carolina Kessler,
  • Julian Heidenreich,
  • Enno Storz,
  • David Pfister,
  • Pia Paffenholz,
  • Yuri Tolkach,
  • Marit Bernhardt,
  • Ralph Wirtz,
  • Markus Eckstein,
  • Axel Heidenreich,
  • Richard Weiten

摘要

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.