pyrimidinones and dinaciclib

Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in patients with TNBC, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell-cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775.. Mono- and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient-derived xenograft (PDX) models with different cyclin E expression profiles. The mechanism(s) of cyclin E-mediated replicative stress were investigated following cyclin E induction or CRISPR/Cas9 knockout by a number of assays in multiple cell lines.. Cyclin E overexpression (i) is enriched in TNBCs with high recurrence rates, (ii) sensitizes TNBC cell lines and PDX models to AZD1775, (iii) leads to CDK2-dependent activation of DNA replication stress pathways, and (iv) increases Wee1 kinase activity. Moreover, treatment of cells with either CDK2 inhibitors or carboplatin leads to transient transcriptional induction of cyclin E (in cyclin E-low tumors) and result in DNA replicative stress. Such drug-mediated cyclin E induction in TNBC cells and PDX models sensitizes them to AZD1775 in a sequential treatment combination strategy.

Topics: Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle Proteins; Cell Line, Tumor; Cyclic N-Oxides; Cyclin E; Disease Models, Animal; DNA Repair; DNA Replication; Drug Resistance, Neoplasm; Gene Expression; Humans; Indolizines; Mice; Mice, Knockout; Models, Biological; Nuclear Proteins; Prognosis; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyridinium Compounds; Pyrimidinones; Stress, Physiological; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays