WEE1 inhibition forces S-phase–arrested cancer cells into mitosis.

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WEE1 inhibition forces S-phase–arrested cancer cells into mitosis. WEE1 inhibition forces S-phase–arrested cancer cells into mitosis. A, assessment of the degree of synergy between gemcitabine and MK-1775 in 25 breast cell lines (23 breast cancer cell lines and 2 breast epithelial cell lines), displayed according to TP53 mutational status. Drug interactions are expressed as a CI. B, SF50 isobolograms of gemcitabine and MK-1775 combination in MCF7 (wild-type TP53) and CAL120 (mutant TP53) cells. C, CAL120 and MCF7 cells were treated with gemcitabine (Gem), MK-1775, or the combination and subjected to dual pH3 (mitotic cells) and PI flow cytometric analysis (FACS). Top, PI alone; bottom, pH3/PI. 2N DNA content indicates cells in G1 phase. 4N DNA content indicates cells in either G2 or M phase. D, CAL120 and MCF7 cells were treated with hydroxyurea (HU) for 24 hours or synchronized (synchr) by a double thymidine block (T) after which MK-1775 was added for an additional 8 hours. Mitotic index was determined by pH3/PI FACS analysis for cells with <4N DNA content (green bars) or cells with 4N DNA content (red bars). E, mitotic index after gemcitabine and MK-1775 combination treatment in various breast cancer cell lines. TP53 status (mutant or wild-type, WT) and CI are indicated for each cell line (*, P < 0.01; Student t test compared with <4N DNA mitotic index of MCF7 cells). Marieke Aarts et al. Cancer Discovery 2012;2:524-539 ©2012 by American Association for Cancer Research