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      Histone deacetylase inhibitor enhances the efficacy of MEK inhibitor through NOXA-mediated MCL1 degradation in triple-negative and inflammatory breast cancer

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          Abstract

          Purpose

          Inflammatory breast cancer (IBC), diagnosed clinically, and triple-negative breast cancer (TNBC), diagnosed by molecular receptor status, are the two most aggressive forms of breast cancer, and both lack effective targeted therapies. We previously demonstrated involvement of histone deacetylase (HDAC) inhibitor entinostat in regulating apoptosis in IBC and TNBC cells; here, we aimed to identify novel combination therapy candidates.

          Experimental Design

          Potential therapeutic targets were identified by mRNA expression profiling of TNBC and IBC cells treated with entinostat. Drug action and synergism were assessed by in vitro proliferation assays, tumor growth in vivo, and proteomic analyses. Gain/loss-of-expression studies were utilized to functionally validate the role of identified targets in sensitivity of TNBC and IBC cells to combination therapy.

          Results

          Entinostat induced activity of the oncogenic ERK pathway and expression of pro-apoptotic NOXA. These are known to stabilize and degrade, respectively, MCL1, an anti-apoptotic Bcl-2 protein. In breast cancer patients, high-MCL1/low-NOXA tumor expression correlated significantly with poor survival outcomes. Combination treatment of entinostat with MEK inhibitor pimasertib reduced the growth of TNBC and IBC cells in vitro and inhibited tumor growth in vivo. The synergistic action of combination therapy was observed in TNBC and IBC cell lines in which NOXA expression was induced following entinostat treatment. The therapeutic activity depended on induction of mitochondrial cell death pathways initiated by NOXA-mediated MCL1 degradation.

          Conclusions

          Our preclinical findings provide a rationale for the clinical testing of combination HDAC and MEK pathway inhibition for TNBC and IBC that exhibit elevated baseline tumor MCL1 expression.

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          Author and article information

          Journal
          9502500
          8794
          Clin Cancer Res
          Clin. Cancer Res.
          Clinical cancer research : an official journal of the American Association for Cancer Research
          1078-0432
          24 May 2017
          02 May 2017
          15 August 2017
          15 August 2018
          : 23
          : 16
          : 4780-4792
          Affiliations
          [1 ]The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas
          [2 ]Section of Translational Breast Cancer Research, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
          [3 ]Syndax Pharmaceuticals, Inc., Waltham, Massachusetts
          Author notes
          [* ]Corresponding authors: Naoto T. Ueno, M.D., Ph.D., Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Breast Medical Oncology, Unit 1354, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009; Tel: (713) 792-2817; Fax: (713) 794-4385; nueno@ 123456mdanderson.org . Jangsoon Lee, Ph.D., Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, Unit 1354, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009; Tel: (713) 745-3601; Fax: (713) 794-4385; jslee@ 123456mdanderson.org
          Article
          PMC5559319 PMC5559319 5559319 nihpa873574
          10.1158/1078-0432.CCR-16-2622
          5559319
          28465444
          909aba91-2939-4bda-9646-0fa469fe9c92
          History
          Categories
          Article

          MCL1,Entinostat,Pimasertib,Inflammatory breast cancer,Triple-negative breast cancer,NOXA/PMAIP1

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