FGFR inhibition as a new therapeutic strategy to sensitize glioblastoma stem cells to tumor treating fields
Abstract Glioblastomas (GBM) are aggressive tumors, which systematically relapse despite standard treatment associating surgery, chemotherapy and radiation therapy. More recently, GBM therapy now includes another therapeutic modality option, Tumor Treating Fields (TTFields) given in combination with...
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Nature Publishing Group
2025-06-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02542-5 |
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| author | Pauline Deshors Ziad Kheil Laetitia Ligat Valerie Gouazé-Andersson Elizabeth Cohen-Jonathan Moyal |
| author_facet | Pauline Deshors Ziad Kheil Laetitia Ligat Valerie Gouazé-Andersson Elizabeth Cohen-Jonathan Moyal |
| author_sort | Pauline Deshors |
| collection | DOAJ |
| description | Abstract Glioblastomas (GBM) are aggressive tumors, which systematically relapse despite standard treatment associating surgery, chemotherapy and radiation therapy. More recently, GBM therapy now includes another therapeutic modality option, Tumor Treating Fields (TTFields) given in combination with Temozolomide (TMZ) following standard treatment. However even with the adjunction of TTFields, GBM remains a lethal disease due to treatment resistance. One of the causes of resistance is the presence of cancer stem cells (GSC) known to be chemo and radioresistant and responsible for tumor regrowth. Studying mechanisms of resistance of GSC to TTFields is thus a major issue to address. Fibroblast Growth Factor Receptors (FGFR) play a major role in numerous processes essential for cancer development, and dysregulation of FGFR signaling has been observed in many cancer types, including GBM. We have previously shown that tyrosine kinase receptor Fibroblast Growth Factor Receptor 1 (FGFR1) controls GBM aggressiveness and GSC radioresistance and that its inhibition leads to radiosensitization through increasing mitotic cell death and microenvironment modulation. Because one of the main mechanisms of action of TTFields is mitotic disturbance and because TTFields act synergistically in vitro with irradiation (IR), we hypothesize that targeting FGFR could sensitize GSC to TTFields. Here we show that, like IR, TTFields significantly decrease GSC growth. Treatment of GSC with pemigatinib (Pem), a FGFR1-3 inhibitor, alters FGFR signalling pathway. We demonstrate that Pem, sensitizes GSC to TTFields by synergistically decreasing their survival and clonogenic ability. Finally, the adjunction of Pem to treatment combining IR and TTFields could sensitize GSC by inducing, in some GSC, a further decrease in the repair of IR-induced DNA damages. Altogether, these results highlight the potential benefits of inhibiting FGFR with the concomitant application of TTFields in the first-line standard GBM treatment to improve patient prognosis. |
| format | Article |
| id | doaj-art-efbca788d0d642e098b1d2e3af3217fc |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-efbca788d0d642e098b1d2e3af3217fc2025-08-20T03:25:15ZengNature Publishing GroupCell Death Discovery2058-77162025-06-0111111110.1038/s41420-025-02542-5FGFR inhibition as a new therapeutic strategy to sensitize glioblastoma stem cells to tumor treating fieldsPauline Deshors0Ziad Kheil1Laetitia Ligat2Valerie Gouazé-Andersson3Elizabeth Cohen-Jonathan Moyal4Oncopole Claudius Regaud, IUCT-Oncopole ToulouseINSERM U1037, Cancer Research Center of Toulouse (CRCT)INSERM U1037, Cancer Research Center of Toulouse (CRCT)Oncopole Claudius Regaud, IUCT-Oncopole ToulouseOncopole Claudius Regaud, IUCT-Oncopole ToulouseAbstract Glioblastomas (GBM) are aggressive tumors, which systematically relapse despite standard treatment associating surgery, chemotherapy and radiation therapy. More recently, GBM therapy now includes another therapeutic modality option, Tumor Treating Fields (TTFields) given in combination with Temozolomide (TMZ) following standard treatment. However even with the adjunction of TTFields, GBM remains a lethal disease due to treatment resistance. One of the causes of resistance is the presence of cancer stem cells (GSC) known to be chemo and radioresistant and responsible for tumor regrowth. Studying mechanisms of resistance of GSC to TTFields is thus a major issue to address. Fibroblast Growth Factor Receptors (FGFR) play a major role in numerous processes essential for cancer development, and dysregulation of FGFR signaling has been observed in many cancer types, including GBM. We have previously shown that tyrosine kinase receptor Fibroblast Growth Factor Receptor 1 (FGFR1) controls GBM aggressiveness and GSC radioresistance and that its inhibition leads to radiosensitization through increasing mitotic cell death and microenvironment modulation. Because one of the main mechanisms of action of TTFields is mitotic disturbance and because TTFields act synergistically in vitro with irradiation (IR), we hypothesize that targeting FGFR could sensitize GSC to TTFields. Here we show that, like IR, TTFields significantly decrease GSC growth. Treatment of GSC with pemigatinib (Pem), a FGFR1-3 inhibitor, alters FGFR signalling pathway. We demonstrate that Pem, sensitizes GSC to TTFields by synergistically decreasing their survival and clonogenic ability. Finally, the adjunction of Pem to treatment combining IR and TTFields could sensitize GSC by inducing, in some GSC, a further decrease in the repair of IR-induced DNA damages. Altogether, these results highlight the potential benefits of inhibiting FGFR with the concomitant application of TTFields in the first-line standard GBM treatment to improve patient prognosis.https://doi.org/10.1038/s41420-025-02542-5 |
| spellingShingle | Pauline Deshors Ziad Kheil Laetitia Ligat Valerie Gouazé-Andersson Elizabeth Cohen-Jonathan Moyal FGFR inhibition as a new therapeutic strategy to sensitize glioblastoma stem cells to tumor treating fields Cell Death Discovery |
| title | FGFR inhibition as a new therapeutic strategy to sensitize glioblastoma stem cells to tumor treating fields |
| title_full | FGFR inhibition as a new therapeutic strategy to sensitize glioblastoma stem cells to tumor treating fields |
| title_fullStr | FGFR inhibition as a new therapeutic strategy to sensitize glioblastoma stem cells to tumor treating fields |
| title_full_unstemmed | FGFR inhibition as a new therapeutic strategy to sensitize glioblastoma stem cells to tumor treating fields |
| title_short | FGFR inhibition as a new therapeutic strategy to sensitize glioblastoma stem cells to tumor treating fields |
| title_sort | fgfr inhibition as a new therapeutic strategy to sensitize glioblastoma stem cells to tumor treating fields |
| url | https://doi.org/10.1038/s41420-025-02542-5 |
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