Cancer cells exhibit a distinct, complementary and aneuploidy-dependent response to Tumor Treating Fields and Spindle Assembly Checkpoint inhibition

Tumor Treating Fields (TTFields) is an FDA-approved cancer therapeutic modality for glioblastoma (GBM) and mesothelioma. TTFields interfere with chromosome segregation by disrupting spindle formation during mitosis. Aneuploidy, an imbalanced chromosome composition, affects the response of cancer cells to spindle assembly checkpoint inhibitors (SACi), and a combination of TTFields and SACi was previously proposed. However, whether these two treatments affect mitosis in the same way, and whether aneuploidy affects the response to TTFields, have yet to be determined. Here, we report that a high degree of aneuploidy exacerbates the response to TTFields. We show that TTF and SACi have different effects on the cell cycle, cell death and gene expression, and that the combination of TTFields and SACi augments the cellular response to treatment. Lastly, we reveal that TTF, and the combination treatment with SACi, result in an upregulation of ion transporters both in vitro and in vivo, and that this upregulation is important for the cellular response to TTFields. Our results therefore suggest that TTFields and SACi induce mitotic aberrations by different mechanisms, that the combination therapy might improve treatment outcome and efficacy, and that this may be particularly relevant for the treatment of aneuploid cancers.

肿瘤治疗电场（Tumor Treating Fields，TTFields）是经美国食品药品监督管理局（FDA）批准的癌症治疗手段，适用于胶质母细胞瘤（GBM）与间皮瘤。TTFields通过破坏有丝分裂过程中的纺锤体形成，干扰染色体分离。非整倍体（aneuploidy）指染色体组成失衡，其会影响癌细胞对纺锤体组装检查点抑制剂（spindle assembly checkpoint inhibitors，SACi）的应答，此前已有研究提出将TTFields与SACi联合使用的治疗策略。然而，这两种治疗方式是否通过相同机制影响有丝分裂，以及非整倍体是否会影响癌细胞对TTFields的应答，仍有待明确。本研究证实，高程度非整倍体会强化细胞对TTFields的应答反应。研究表明，TTFields与SACi对细胞周期、细胞死亡及基因表达的调控作用存在差异，二者联合使用可增强细胞对治疗的应答效果。此外，本研究还发现，无论在体外还是体内环境中，TTFields单药及与SACi的联合治疗均会上调离子转运体的表达，且该表达上调对细胞应答TTFields治疗至关重要。综上，本研究结果提示：TTFields与SACi通过不同机制诱导有丝分裂异常；二者联合疗法或可改善治疗结局与疗效；这一发现或对非整倍体恶性肿瘤的治疗具有重要参考价值。