Role of the PI3K/AKT signaling pathway in the cellular response to Tumor Treating Fields (TTFields)
Abstract Tumor Treating Fields (TTFields) are electric fields that induce cancer cell death. Genomic analysis of glioblastoma tumors resected from TTFields-treated patients suggested a potential link between a reduced or absent response to TTFields and activating mutations in the phosphatidylinosito...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-03-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07546-8 |
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| author | Anat Klein-Goldberg Tali Voloshin Efrat Zemer Tov Rom Paz Lina Somri-Gannam Alexandra Volodin Lilach Koren Lena Lifshitz Aviv Meir Ayelet Shabtay-Orbach Roni Blatt Shay Cahal Catherine Tempel-Brami Kerem Wainer-Katsir Tal Kan Bella Koltun Boris Brant Yiftah Barsheshet Adi Haber Moshe Giladi Uri Weinberg Yoram Palti |
| author_facet | Anat Klein-Goldberg Tali Voloshin Efrat Zemer Tov Rom Paz Lina Somri-Gannam Alexandra Volodin Lilach Koren Lena Lifshitz Aviv Meir Ayelet Shabtay-Orbach Roni Blatt Shay Cahal Catherine Tempel-Brami Kerem Wainer-Katsir Tal Kan Bella Koltun Boris Brant Yiftah Barsheshet Adi Haber Moshe Giladi Uri Weinberg Yoram Palti |
| author_sort | Anat Klein-Goldberg |
| collection | DOAJ |
| description | Abstract Tumor Treating Fields (TTFields) are electric fields that induce cancer cell death. Genomic analysis of glioblastoma tumors resected from TTFields-treated patients suggested a potential link between a reduced or absent response to TTFields and activating mutations in the phosphatidylinositol 3-kinase (PI3K) p110α subunit (PIK3CA). Our study aimed to investigate the role of the PI3K/AKT pathway in the response to TTFields. We tested changes in signaling pathways in control versus TTFields-treated U-87 MG glioblastoma, A2780 ovarian carcinoma, and H1299 non-small cell lung cancer (NSCLC) cells using the Luminex multiplex assay, validated by western blot analysis and inhibition assays. We also performed in vivo validation using immunohistochemistry on tumor sections from animals bearing orthotopic N1-S1 hepatocellular, MOSE-L ovarian, or LL/2 lung tumors that were treated with TTFields or sham. Finally, we examined the efficacy of concomitant treatment with TTFields and PI3K inhibitors in cell lines and mouse models. Our findings elucidate the mechanisms driving PI3K/AKT activation following TTFields treatment, revealing that the AKT signaling amplitude increases over time and is influenced by cell-surface and cell-cell interactions. Specifically, focal adhesion kinase (FAK) and N-cadherin were found to promote AKT phosphorylation, activating cell survival pathways. Furthermore, our investigation revealed that pharmacological inhibition of PI3K sensitized cancer cells to TTFields, both in vitro and in vivo. Our research suggests that the PI3K/AKT pathway is involved in cancer cell response to TTFields, and that inhibition of this pathway may serve as a potential therapeutic target for sensitizing cancer cells to TTFields. |
| format | Article |
| id | doaj-art-a30a2a4d23bc49888ec9aa85538dc5e3 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-a30a2a4d23bc49888ec9aa85538dc5e32025-08-20T02:49:16ZengNature Publishing GroupCell Death and Disease2041-48892025-03-0116111310.1038/s41419-025-07546-8Role of the PI3K/AKT signaling pathway in the cellular response to Tumor Treating Fields (TTFields)Anat Klein-Goldberg0Tali Voloshin1Efrat Zemer Tov2Rom Paz3Lina Somri-Gannam4Alexandra Volodin5Lilach Koren6Lena Lifshitz7Aviv Meir8Ayelet Shabtay-Orbach9Roni Blatt10Shay Cahal11Catherine Tempel-Brami12Kerem Wainer-Katsir13Tal Kan14Bella Koltun15Boris Brant16Yiftah Barsheshet17Adi Haber18Moshe Giladi19Uri Weinberg20Yoram Palti21Novocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdNovocure LtdAbstract Tumor Treating Fields (TTFields) are electric fields that induce cancer cell death. Genomic analysis of glioblastoma tumors resected from TTFields-treated patients suggested a potential link between a reduced or absent response to TTFields and activating mutations in the phosphatidylinositol 3-kinase (PI3K) p110α subunit (PIK3CA). Our study aimed to investigate the role of the PI3K/AKT pathway in the response to TTFields. We tested changes in signaling pathways in control versus TTFields-treated U-87 MG glioblastoma, A2780 ovarian carcinoma, and H1299 non-small cell lung cancer (NSCLC) cells using the Luminex multiplex assay, validated by western blot analysis and inhibition assays. We also performed in vivo validation using immunohistochemistry on tumor sections from animals bearing orthotopic N1-S1 hepatocellular, MOSE-L ovarian, or LL/2 lung tumors that were treated with TTFields or sham. Finally, we examined the efficacy of concomitant treatment with TTFields and PI3K inhibitors in cell lines and mouse models. Our findings elucidate the mechanisms driving PI3K/AKT activation following TTFields treatment, revealing that the AKT signaling amplitude increases over time and is influenced by cell-surface and cell-cell interactions. Specifically, focal adhesion kinase (FAK) and N-cadherin were found to promote AKT phosphorylation, activating cell survival pathways. Furthermore, our investigation revealed that pharmacological inhibition of PI3K sensitized cancer cells to TTFields, both in vitro and in vivo. Our research suggests that the PI3K/AKT pathway is involved in cancer cell response to TTFields, and that inhibition of this pathway may serve as a potential therapeutic target for sensitizing cancer cells to TTFields.https://doi.org/10.1038/s41419-025-07546-8 |
| spellingShingle | Anat Klein-Goldberg Tali Voloshin Efrat Zemer Tov Rom Paz Lina Somri-Gannam Alexandra Volodin Lilach Koren Lena Lifshitz Aviv Meir Ayelet Shabtay-Orbach Roni Blatt Shay Cahal Catherine Tempel-Brami Kerem Wainer-Katsir Tal Kan Bella Koltun Boris Brant Yiftah Barsheshet Adi Haber Moshe Giladi Uri Weinberg Yoram Palti Role of the PI3K/AKT signaling pathway in the cellular response to Tumor Treating Fields (TTFields) Cell Death and Disease |
| title | Role of the PI3K/AKT signaling pathway in the cellular response to Tumor Treating Fields (TTFields) |
| title_full | Role of the PI3K/AKT signaling pathway in the cellular response to Tumor Treating Fields (TTFields) |
| title_fullStr | Role of the PI3K/AKT signaling pathway in the cellular response to Tumor Treating Fields (TTFields) |
| title_full_unstemmed | Role of the PI3K/AKT signaling pathway in the cellular response to Tumor Treating Fields (TTFields) |
| title_short | Role of the PI3K/AKT signaling pathway in the cellular response to Tumor Treating Fields (TTFields) |
| title_sort | role of the pi3k akt signaling pathway in the cellular response to tumor treating fields ttfields |
| url | https://doi.org/10.1038/s41419-025-07546-8 |
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