ro-3306 and Breast-Neoplasms

Inhibition of the protein kinase WEE1 synergizes with chemotherapy in preclinical models and WEE1 inhibitors are being explored as potential cancer therapies. Here, we investigate the mechanism that underlies this synergy. We show that WEE1 inhibition forces S-phase-arrested cells directly into mitosis without completing DNA synthesis, resulting in highly abnormal mitoses characterized by dispersed chromosomes and disorganized bipolar spindles, ultimately resulting in mitotic exit with gross micronuclei formation and apoptosis. This mechanism of cell death is shared by CHK1 inhibitors, and combined WEE1 and CHK1 inhibition forces mitotic entry from S-phase in the absence of chemotherapy. We show that p53/p21 inactivation combined with high expression of mitotic cyclins and EZH2 predispose to mitotic entry during S-phase with cells reliant on WEE1 to prevent premature cyclin-dependent kinase (CDK)1 activation. These features are characteristic of aggressive breast, and other, cancers for which WEE1 inhibitor combinations represent a promising targeted therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Cycle Proteins; Cell Line; Cell Line, Tumor; Checkpoint Kinase 1; Cyclins; Deoxycytidine; DNA-Binding Proteins; Enhancer of Zeste Homolog 2 Protein; Female; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, SCID; Mitosis; Nuclear Proteins; Polycomb Repressive Complex 2; Protein Kinase Inhibitors; Protein Kinases; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Quinolines; S Phase; Thiazoles; Thiophenes; Transcription Factors; Tumor Burden; Tumor Suppressor Protein p53; Urea; Xenograft Model Antitumor Assays