Tumor Treating Fields (TTFields) downregulate the Fanconi Anemia-BRCA pathway and increase the efficacy of chemotherapy in malignant pleural mesothelioma preclinical models
Tumor Treating Fields (TTFields) downregulate the Fanconi Anemia-BRCA pathway and increase the efficacy of chemotherapy in malignant pleural mesothelioma preclinical models
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DOI：
10.1016/j.lungcan.2021.08.011
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发表时间：
2021-09-03
期刊：
影响因子：
5.3
通讯作者：
Palti, Yoram
中科院分区：
文献类型：
--
作者：
Mumblat, Helena;Martinez-Conde, Antonia;Palti, Yoram
目的：肿瘤治疗电场（TTFields）是一种低强度、中频、交变电场，对癌细胞具有抗有丝分裂作用。TTFields联合培美曲塞和铂类药物在美国和欧盟获批作为不可切除的局部晚期或转移性恶性胸膜间皮瘤（MPM）的一线治疗。本研究的目的是表征TTFields在MPM细胞系和动物模型中的作用机制。方法：用TTFields处理人MPM细胞系MSTO-211 H和NCI-H2052，以确定产生最大细胞毒性的频率。检查了TTFields对DNA损伤和修复的影响，以及TTFields与顺铂和/或培美曲塞联合用药的细胞毒性作用。在原位IL-45和皮下RN 5小鼠模型中评价了TTFields联合顺铂和培美曲塞的疗效。结果：频率为150 kHz的TTFields对MPM细胞的细胞毒性最高。应用150 kHz TTFields导致DNA双链断裂形成增加，DNA损伤诱导细胞周期阻滞蛋白表达升高，范可尼贫血（FA）-BRCA DNA修复途径蛋白表达降低。TTFields与顺铂或培美曲塞联合治疗与每种方式单独治疗相比，显著增加了治疗疗效，TTFields-培美曲塞和TTFields-顺铂联合治疗分别表现出相加作用和协同作用。在动物模型中，TTFields-顺铂-培美曲塞联合治疗组的肿瘤体积显著低于对照组，同时肿瘤内DNA损伤增加。结论：该研究表明，TTFields治疗MPM的疗效与FA-BRCA通路蛋白表达减少和DNA损伤增加相关。该作用机制与观察到的TTFields-顺铂协同作用与TTFields-培美曲塞相加作用一致，因为顺铂诱导的DNA损伤通过FA-BRCA途径修复。
Objectives: Tumor Treating Fields (TTFields) are low intensity, intermediate frequency, alternating electric fields with antimitotic effects on cancerous cells. TTFields concomitant with pemetrexed and a platinum agent are approved in the US and EU as first line therapy for unresectable, locally advanced or metastatic malignant pleural mesothelioma (MPM). The goal of the current study was to characterize the mechanism of action of TTFields in MPM cell lines and animal models. Methods: Human MPM cell lines MSTO-211H and NCI-H2052 were treated with TTFields to determine the frequency that elicits maximal cytotoxicity. The effect of TTFields on DNA damage and repair, and the cytotoxic effect of TTFields in combination with cisplatin and/or pemetrexed were examined. Efficacy of TTFields concomitant with cisplatin and pemetrexed was evaluated in orthotopic IL-45 and subcutaneous RN5 murine models. Results: TTFields at a frequency of 150 kHz demonstrated the highest cytotoxicity to MPM cells. Application of 150 kHz TTFields resulted in increased formation of DNA double strand breaks, elevated expression of DNA damage induced cell cycle arrest proteins, and reduced expression of Fanconi Anemia (FA)-BRCA DNA repair pathway proteins. Co-treatment of TTFields with cisplatin or pemetrexed significantly increased treatment efficacy versus each modality alone, with additivity and synergy exhibited by the TTFields-pemetrexed and TTFields-cisplatin combinations, respectively. In animal models, tumor volume was significantly lower for the TTFields-cisplatin-pemetrexed combination compared to control, accompanied by increased DNA damage within the tumor. Conclusion: This research demonstrated that the efficacy of TTFields for the treatment of MPM is associated with reduced expression of FA-BRCA pathway proteins and increased DNA damage. This mechanism of action is consistent with the observed synergism for TTFields-cisplatin vs additivity for TTFields-pemetrexed, as cisplatininduced DNA damage is repaired via the FA-BRCA pathway.