PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer

Cancer Letters
Daniela De MartinoAntonio Di Cristofano

Abstract

Anaplastic thyroid cancer (ATC) is among the most lethal malignancies. The mitotic kinase PLK1 is overexpressed in the majority of ATCs and PLK1 inhibitors have shown preclinical efficacy. However, they also cause mitotic slippage and endoreduplication, leading to the generation of tetraploid, genetically unstable cell populations. We hypothesized that PI3K activity may facilitate mitotic slippage upon PLK1 inhibition, and thus tested the effect of combining PLK1 and PI3K inhibitors in ATC models, in vitro and in vivo. Treatment with BI6727 and BKM120 resulted in a significant synergistic effect in ATC cells, independent of the levels of AKT activity. Combination of the two drugs enhanced growth suppression at doses for which the single drugs showed no effect, and led to a massive reduction of the tetraploid cells population. Furthermore, combined treatment in PI3Khigh cell lines showed a significant induction of apoptosis. Finally, combined inhibition of PI3K and PLK1 was extremely effective in vivo, in an immunocompetent allograft model of ATC. Our results demonstrate a clear therapeutic potential of combining PLK1 and PI3K inhibitors in anaplastic thyroid tumors.

Citations

Nov 6, 2018·The Journal of Clinical Investigation·Quais N HassanJohn C Byrd
Jul 13, 2019·Future Medicinal Chemistry·Inas Elsayed, Xiaosheng Wang
Jun 13, 2019·Blood Advances·Carlos Murga-ZamalloaRyan A Wilcox
Jun 20, 2020·Molecular Cancer Research : MCR·Eric L BolfFrances E Carr
Dec 12, 2020·Cancer Science·Shu-Fu LinRichard J Wong
Feb 24, 2021·International Journal of Radiation Oncology, Biology, Physics·Baiyao WangYawei Yuan

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