Klein-Goldberg Anat, Voloshin Tali, Zemer Tov Efrat, Paz Rom, Somri-Gannam Lina, Volodin Alexandra, Koren Lilach, Lifshitz Lena, Meir Aviv, Shabtay-Orbach Ayelet, Blatt Roni, Cahal Shay, Tempel-Brami Catherine, Wainer-Katsir Kerem, Kan Tal, Koltun Bella, Brant Boris, Barsheshet Yiftah, Haber Adi, Giladi Moshe, Weinberg Uri, Palti Yoram
Novocure Ltd, Haifa, Israel.
Cell Death Dis. 2025 Mar 27;16(1):210. doi: 10.1038/s41419-025-07546-8.
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.
肿瘤治疗电场（TTFields）是诱导癌细胞死亡的电场。对从接受TTFields治疗的患者身上切除的胶质母细胞瘤肿瘤进行的基因组分析表明，对TTFields反应减弱或无反应与磷脂酰肌醇3激酶（PI3K）p110α亚基（PIK3CA）的激活突变之间可能存在联系。我们的研究旨在调查PI3K/AKT通路在对TTFields反应中的作用。我们使用Luminex多重检测法测试了对照细胞与接受TTFields治疗的U-87 MG胶质母细胞瘤细胞、A2780卵巢癌细胞和H1299非小细胞肺癌（NSCLC）细胞中信号通路的变化，并通过蛋白质免疫印迹分析和抑制试验进行了验证。我们还使用免疫组织化学对接受TTFields或假处理的原位N1-S1肝细胞癌、MOSE-L卵巢癌或LL/2肺癌动物模型的肿瘤切片进行了体内验证。最后，我们研究了TTFields与PI3K抑制剂联合治疗在细胞系和小鼠模型中的疗效。我们的研究结果阐明了TTFields治疗后驱动PI3K/AKT激活的机制，表明AKT信号幅度随时间增加，并受细胞表面和细胞间相互作用的影响。具体而言，发现粘着斑激酶（FAK）和N-钙粘蛋白可促进AKT磷酸化，激活细胞存活通路。此外，我们的研究表明，PI3K的药理学抑制使癌细胞在体外和体内对TTFields敏感。我们的研究表明，PI3K/AKT通路参与癌细胞对TTFields的反应，抑制该通路可能作为使癌细胞对TTFields敏感的潜在治疗靶点。
