dinaciclib and Inflammatory-Breast-Neoplasms

Inflammatory breast cancer (IBC) is a virulent form of breast cancer, and novel treatment strategies are urgently needed. Immunohistochemical analysis of tumors from women with a clinical diagnosis of IBC (n = 147) and those with non-IBC breast cancer (n = 2510) revealed that, whereas in non-IBC cases cytoplasmic cyclin E was highly correlated with poor prognosis (P < 0.001), in IBC cases both nuclear and cytoplasmic cyclin E were indicative of poor prognosis. These results underscored the utility of the cyclin E/CDK2 complex as a novel target for treatment. Because IBC cell lines were highly sensitive to the CDK2 inhibitors dinaciclib and meriolin 5, we developed a high-throughput survival assay (HTSA) to design novel sequential combination strategies based on the presence of cyclin E and CDK2. Using a 14-cell-line panel, we found that dinaciclib potentiated the activity of DNA-damaging chemotherapies treated in a sequence of dinaciclib followed by chemotherapy, whereas this was not true for paclitaxel. We also identified a signature of DNA repair-related genes that are downregulated by dinaciclib, suggesting that global DNA repair is inhibited and that prolonged DNA damage leads to apoptosis. Taken together, our findings argue that CDK2-targeted combinations may be viable strategies in IBC worthy of future clinical investigation.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle; Cell Proliferation; Combined Modality Therapy; Cyclic N-Oxides; Cyclin E; Cyclin-Dependent Kinase 2; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Indolizines; Inflammatory Breast Neoplasms; Middle Aged; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Staging; Oncogene Proteins; Prognosis; Pyridinium Compounds; Survival Rate; Tumor Cells, Cultured; Young Adult