Histone Deacetylase Inhibitor Enhances the Efficacy of MEK Inhibitor through NOXA-Mediated MCL1 Degradation in Triple-Negative and Inflammatory Breast Cancer.

摘要: Purpose: Inflammatory breast cancer (IBC), diagnosed clinically, and triple-negative (TNBC), by molecular receptor status, are the two most aggressive forms of cancer, both lack effective targeted therapies. We previously demonstrated involvement histone deacetylase (HDAC) inhibitor entinostat in regulating apoptosis IBC TNBC cells; here, we aimed to identify novel combination therapy candidates. Experimental Design: Potential therapeutic targets were identified mRNA expression profiling cells treated with entinostat. Drug action synergism assessed vitro proliferation assays, tumor growth vivo , proteomic analyses. Gain/loss-of-expression studies utilized functionally validate role sensitivity therapy. Results: Entinostat induced activity oncogenic ERK pathway proapoptotic NOXA. These known stabilize degrade, respectively, MCL1, an antiapoptotic Bcl-2 protein. In patients, high-MCL1/low-NOXA correlated significantly poor survival outcomes. Combination treatment MEK pimasertib reduced inhibited . The synergistic was observed cell lines which NOXA following treatment. depended on induction mitochondrial death pathways initiated NOXA-mediated MCL1 degradation. Conclusions: Our preclinical findings provide a rationale for clinical testing HDAC inhibition that exhibit elevated baseline expression. Clin Cancer Res; 1–13. ©2017 AACR.