Marson, CM; Koo, CY; Reyes-Corral, M; Olmos, Y; Tavares, IA; Linardopoulos, S; Tutt, A; Marson, CM; Koo, CY; Reyes-Corral, M; Olmos, Y; Tavares, IA; Linardopoulos, S; Tutt, A; Morris, ADH; - view fewer (2017) Targeting TAO kinases using a new inhibitor compound delays mitosis and induces mitotic cell death in centrosome amplified breast cells. Molecular Cancer Therapeutics , 16 (11) pp. 2410-2421. 10.1158/1535-7163.MCT-17-0077.

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Abstract

Thousand-and-one amino acid kinases (TAOKs) 1 and 2 are activated catalytically during mitosis and can contribute to mitotic cell rounding and spindle positioning. Here, we characterize a compound that inhibits TAOK1 and TAOK2 activity with IC50 values of 11-15 nM, is ATP-competitive and targets these kinases selectively. TAOK inhibition or depletion in centrosome amplified SKBR3 or BT549 breast cancer cell models increases the mitotic population, the percentages of mitotic cells displaying amplified centrosomes and multipolar spindles, induces cell death and inhibits cell growth. In contrast, non-tumorigenic and dividing bipolar MCF-10A breast cells appear less dependent on TAOK activity and can complete mitosis and proliferate in the presence of the TAOK inhibitor. We demonstrate that TAOK1 and TAOK2 localize to the cytoplasm and centrosomes respectively during mitosis. Live cell imaging shows that the TAOK inhibitor prolongs the duration of mitosis in SKBR3 cells, increases mitotic cell death and reduces the percentages of cells exiting mitosis, whereas MCF-10A cells continue to divide and proliferate. Over 80% of breast cancer tissues display supernumerary centrosomes and tumor cells frequently cluster extra centrosomes to avoid multipolar mitoses and associated cell death. Consequently, drugs that stimulate centrosome declustering and induce multipolarity are likely to target dividing centrosome amplified cancer cells preferentially, whilst sparing normal bipolar cells. Our results demonstrate that TAOK inhibition can enhance centrosome declustering and mitotic catastrophe in cancer cells and these proteins may therefore offer novel therapeutic targets suitable for drug inhibition and the potential treatment of breast cancers, where supernumerary centrosomes occur.

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