| RRC ID |
86330
|
| 著者 |
Kucerova L, Fekiacova A, Udvorkova N, Malcharkova P, Blahova V, Jochova S, Kalavska K, Cierna Z, Mego M.
|
| タイトル |
Mirvetuximab Soravtansine Induces Potent Cytotoxicity and Bystander Effect in Cisplatin-Resistant Germ Cell Tumor Cells.
|
| ジャーナル |
Cells
|
| 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.
|
| 巻・号 |
14(4)
|
| 公開日 |
2025-2-15
|
| DOI |
10.3390/cells14040287
|
| PII |
cells14040287
|
| PMID |
39996761
|
| PMC |
PMC11853988
|
| MeSH |
Animals
Antibodies, Monoclonal, Humanized* / pharmacology
Antibodies, Monoclonal, Humanized* / therapeutic use
Apoptosis / drug effects
Bystander Effect* / drug effects
Cell Line, Tumor
Cisplatin* / pharmacology
Drug Resistance, Neoplasm* / drug effects
Folate Receptor 1 / genetics
Folate Receptor 1 / metabolism
Humans
Immunoconjugates* / pharmacology
Immunoconjugates* / therapeutic use
Male
Maytansine* / analogs & derivatives
Maytansine* / pharmacology
Maytansine* / therapeutic use
Mice
Mice, Nude
Neoplasms, Germ Cell and Embryonal* / drug therapy
Neoplasms, Germ Cell and Embryonal* / genetics
Neoplasms, Germ Cell and Embryonal* / metabolism
Neoplasms, Germ Cell and Embryonal* / pathology
Testicular Neoplasms* / drug therapy
Testicular Neoplasms* / genetics
Testicular Neoplasms* / metabolism
Testicular Neoplasms* / pathology
Xenograft Model Antitumor Assays
|
| IF |
4.366
|
| リソース情報 |
| ヒト・動物細胞 |
NEC8(RCB0489) |
