Targeting Epigenetic Regulators as a Novel Means to Prevent Triple Negative Breast Cancer Recurrence

Despite effective treatments, triple-negative breast cancer (TNBC) frequently recurs, causing mortality. Using multiple TNBC models, we studied recurrence mechanisms by examining recovery from clinically relevant concentrations of standard-of-care chemotherapies. Lineage barcode tracking shows recovery occurs stochastically, suggesting each cell in the initial population can recover. Single-cell RNA-sequencing of barcoded cells and Western blotting revealed epigenetic pathways altered during recovery from chemotherapy exposure. In cell culture, several epi-drugs and senolytic ABT-263 were most effective when administered after chemotherapy exposure, compared to combination or prior use. In contrast, only the KAT inhibitor MG149 controlled tumor growth when used sequentially in tumor-bearing mice. Analysis of post-chemotherapy tumors suggests the ineffectiveness of many drugs in vivo could be due to low levels of therapy-induced cell stress states, including senescence and autophagy. In vitro and in vivo studies showed sequential use of MG149 after Doxorubicin increased apoptosis, reduced cells in G2/M DNA damage checkpoint, and reduced expression of cell cycle inhibitors p21, p27, and p53. MG149's efficacy depends on gain of function (GOF) p53 mutation and KAT8, which enhances pro-apoptotic factors PUMA, BAX, and BAK. This enhancement occurs through GOF p53 degradation, leading to tumor cell death following chemotherapy. Our findings indicate select epigenetic states form after chemotherapy exposure and demonstrate that sequential epigenetic therapies can be therapeutically targeted to prevent TNBC recurrence. This strategy could repurpose epi-drugs previously unsuccessful in controlling solid tumor growth when used with chemotherapy.