2. Academic Validation
  3. Mirvetuximab Soravtansine Induces Potent Cytotoxicity and Bystander Effect in Cisplatin-Resistant Germ Cell Tumor Cells

Mirvetuximab Soravtansine Induces Potent Cytotoxicity and Bystander Effect in Cisplatin-Resistant Germ Cell Tumor Cells

  • Cells. 2025 Feb 15;14(4):287. doi: 10.3390/cells14040287.
Lucia Kucerova 1 2,  Adriana Fekiacova 1 3,  Natalia Udvorkova 1 2 4,  Pavlina Malcharkova 1,  Viktoria Blahova 1,  Silvia Jochova 2,  Katarina Kalavska 1,  Zuzana Cierna 5 6,  Michal Mego 1
Affiliations

Affiliations

  • 1 Translational Research Unit, 2nd Oncology Clinic of the Medical Faculty, Comenius University, and the National Cancer Institute, Klenova 1, 833 10 Bratislava, Slovakia.
  • 2 Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia.
  • 3 Department of Genetics, Faculty of Natural Sciences, Comenius University, 841 04 Bratislava, Slovakia.
  • 4 Medical Faculty, Comenius University, 813 72 Bratislava, Slovakia.
  • 5 Department of Pathology, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia.
  • 6 Department of Pathology, Faculty of Health Care and Social Work, University Hospital, 917 75 Trnava, Slovakia.
PMID: 39996761 DOI: 10.3390/cells14040287
Abstract

Patients with treatment-refractory/relapsing germ cell tumors (GCTs) have a dismal prognosis due to a lack of any effective therapy. Moreover, the efficacy of newly approved targeted therapies remains unexplored for cisplatin-resistant GCTs. Previously, it was demonstrated that folate receptor α (FRα) is overexpressed in many tumor types and efficiently targeted by the antibody-drug conjugate (ADC) mirvetuximab soravtansine (MIRV) in cisplatin-resistant cancers. We hypothesized that FRα represents an attractive target for treating treatment-refractory GCTs. We determined the expression of the FOLR1 gene in a broad range of GCT cell lines and tumor xenografts. We tested the antitumor efficacy of MIRV on cisplatin-resistant GCT cells in vitro and explored the ability of MIRV treatment to induce a bystander effect in the direct coculture of FRα-high and FRα-low cells. We found that the FOLR1 gene has significantly higher expression in testicular GCTs (TGCTs) than in normal testicular tissue. FOLR1 is highly expressed in the TCam2, JEG3, JAR, and NOY1 cell lines and their respective cisplatin-resistant variants. MIRV treatment induced Apoptosis and a potent antiproliferative effect in cisplatin-resistant GCT cells in adherent and 3D spheroid cultures in vitro. A significant decrease in FRα-low 2102EP_R_NL cells was observed in the presence of FRα-high NOY1_R_SK in the presence of 12.5 nM MIRV, showing a potent bystander effect in the direct coculture. Immunohistochemical analysis confirmed significantly higher Folr1 protein expression in patients with TGCTs postchemotherapy than in chemo-naïve patients, as well as in patients with an unfavorable prognosis. In this study, we present data suggesting that the FOLR1 gene is highly expressed in (T)GCT cells in vitro and in vivo, and anti-FRα-targeting therapies should be investigated as a treatment modality in a subset of patients with TGCTs. Moreover, MIRV induced significant antitumor and bystander effects, thus showing its potential in further preclinical exploration and drug repurposing for a salvage treatment regime in refractory (T)GCT disease.

Keywords

antibody–drug conjugate; bystander effect; chemoresistance; cisplatin; germ cell tumors; mirvetuximab soravtansine.

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