Sensitization of Resistant Breast Cancer Cells with a Jumonji Family Histone Demethylase Inhibitor

SIMPLE SUMMARY: Using a cell culture model of resistant breast cancer cells with the phenotype that is often responsible for the early relapse of triple-negative breast cancer, namely, the persistence of these cells in reversible quiescence under a variety of challenges, we found that reprogramming the epigenome by treatment with JIB-04, a small-molecule inhibitor of Jumonji-family histone demethylases, sensitized resistant cells. We used this model of deep intrinsic resistance featuring many molecular mechanisms of achieving this phenotype to perform lengthy evaluations of less cytotoxic doses of JIB-04. We found that resistant cells derived from triple-negative inflammatory breast cancer cell lines were either much more sensitive to JIB-04 than the parental cell line or altered by the treatment such that they became sensitive to the chemotherapeutic drugs paclitaxel and doxorubicin. Notably, JIB-04 exposure increased PD-L1 expression in cancer cells, which means that JIB-04 may have clinical applications in improving the responses of triple-negative breast cancer to anti-PD-L1 therapy. ABSTRACT: In the present study, we evaluated JIB-04, a small-molecule epigenetic inhibitor initially discovered to inhibit cancer growth, to determine its ability to affect deep intrinsic resistance in a breast cancer model. The model was based on a function-based approach to the selection of cancer cells in a cell culture that can survive a variety of challenges in prolonged, but reversible, quiescence. These resistant cancer cells possessed a variety of mechanisms, including modifications of the epigenome and transcriptome, for generating a high degree of cellular heterogeneity. We found that long pretreatment with JIB-04 sensitized resistant triple-negative inflammatory breast cancer cells and their parental cell line SUM149 to the chemotherapeutic drugs doxorubicin and paclitaxel. Resistant cancer cells derived from another inflammatory breast cancer cell line, FC-IBC02, were considerably more sensitive to JIB-04 than the parental cell line. Investigating a mechanism of sensitization, we found that JIB-04 exposure increased the expression of PD-L1 in resistant cells, suggesting that JIB-04 may also sensitize resistant breast cancer cells to anti-PD-L1 immune therapy. Finally, these results support the usefulness of a cell culture-based experimental strategy for evaluating anticancer agents, such as JIB-04, that may halt cancer evolution and prevent the development of cancer resistance to currently used therapies.