Testing the effectiveness of KDM4A inhibitors on triple negative breast cancer cell lines
Triple negative breast cancer (TNBC) is an aggressive form of cancer in which the patient’s breast tissue lacks estrogen, progesterone, and human epidermal growth factor-2 receptors. The absence of these hormone receptors prevents treatments using standard hormone therapies and the 5-year survival rate is 8-16% lower than other breast cancer subtypes. Lysine-specific demethylase 4A (KDM4A) is an epigenetic histone modifying enzyme that demethylates H3K9me3/me2 and H3K36me3/me2; when it is overexpressed, it facilitates tumor growth. The goal of this project was to test if TGN-3062, a KDM4A inhibitor designed and synthesized at TGen, can improve current TNBC treatments. Three TNBC cell lines (MDA-MB-231, MDA-MB-436, MDA-MB-468) were cultured and dosed with varying concentrations of TGN-3062 and/or a cytotoxic drug that is either currently in clinical trials or established as a treatment for TNBC. The drugs included in this study were Olaparib, Osimertinib, Afatinib, Carboplatin, and Paclitaxel. Protein expression levels though western blot confirmed KDM4A expression in all three TNBC cell lines. There were also changes in the global H3K36me3/me2 profile upon treatment with TGN-3067 (prodrug of TGN-3062). The Bliss synergy model indicated that targeted therapeutics tested in this study—Olaparib, Osimertinib, and Afatinib—demonstrated noteworthy synergy with TGN-3067. The chemotherapeutics Carboplatin and Paclitaxel also demonstrated moderate synergy with TGN-3067. These findings suggest the potential for KDM4A inhibitors to be used within a clinical setting to create a better prognosis for TNBC patients.
