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.