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Abstract Glioblastoma (GBM) is a highly malignant brain tumor, and conventional treatments such as surgical resection and chemotherapy have limited effectiveness, with a high rate of recurrence and poor prognosis for patients. In 2011, the FDA approved a novel therapy for recurrent GBM known as Tumor Treating Fields (TTFields). TTFields use alternating intermediate-frequency (200 kHz) and low-intensity (1-3 V/cm) electric fields to interfere with tumor cells, inducing apoptosis and inhibiting tumor growth. This study aimed to explore the molecular mechanisms of TTFields therapy at the systems biology level using quantitative proteomics technology. We analyzed U87 cells before and after TTFields treatment using quantitative proteomics and identified a total of 7679 proteins. Among them, 804 proteins were significantly upregulated after TTFields treatment, and 1141 proteins were significantly downregulated. Pathway enrichment analysis of differentially expressed proteins showed that upregulated proteins were mainly associated with cell proliferation, cell cycle, and transcription, possibly representing compensatory responses to the TTFields treatment. Further analysis revealed a significant upregulation of the tumor proliferation key protein PARP1, which was validated by protein immunoblotting experiments. Based on this analysis, we hypothesized that combining TTFields with Olaparib (a PARP1 inhibitor) might enhance the sensitivity of TTFields. Subsequently, we performed cell proliferation experiments to evaluate the concomitant application strategy, and the results demonstrated that Olaparib in combination with TTFields treatment significantly reduced the survival rate of U87 cells compared to single-drug treatment. In conclusion, using quantitative proteomics, this study revealed the biological processes underlying the inhibitory effects of TTFields on GBM proliferation. Under TTFields intervention, the expression of PARP1 was upregulated, and the use of a PARP1 inhibitor in combination significantly increased the sensitivity of TTFields. Therefore, this study not only elucidated the molecular mechanisms of TTFields therapy for GBM treatment at the systems biology level, but also provided support for further enhancing the efficacy of TTFields. Citation Format: Qi Mei, Yanmei Gao, Rong Li, Chenxu Wang, Guangyuan Hu, He Huang. Quantitative proteomics reveal the mechanism of TTFields therapy for glioblastoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 7100.
Mei et al. (Fri,) studied this question.