TY - JOUR
T1 - Histone deacetylase inhibitor enhances the efficacy of MEK inhibitor through NOXA-mediated MCL1 degradation in triple-negative and inflammatory breast cancer
AU - Torres-Adorno, Angie M.
AU - Lee, Jangsoon
AU - Kogawa, Takahiro
AU - Ordentlich, Peter
AU - Tripathy, Debu
AU - Lim, Bora
AU - Ueno, Naoto T.
N1 - Funding Information:
We thank Sunita Patterson and Christopher Graber of the Department of Scientific Publications and Dr. Bedrich Eckhardt of the Department of Breast Medical Oncology at the MD Anderson Cancer Center for their expert editorial assistance. Entinostat was provided by Syndax Pharmaceuticals Inc. Pimasertib was provided by EMD Serono, Inc., an affiliate of Merck KGaA, Germany.
Funding Information:
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): A.M. Torres-Adorno, J. Lee, T. Kogawa Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A.M. Torres-Adorno, J. Lee, T. Kogawa, D. Tripathy, N.T. Ueno Writing, review, and/or revision of the manuscript: A.M. Torres-Adorno, J. Lee, T. Kogawa, P. Ordentlich, D. Tripathy, B. Lim, N.T. Ueno Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): A.M. Torres-Adorno, T. Kogawa, N.T. Ueno Study supervision: J. Lee, N.T. Ueno Other (project coordinator): A.M. Torres-Adorno
Funding Information:
This work was supported by the Morgan Welch Inflammatory Breast Cancer Research Program, the State of Texas Rare and Aggressive Breast Cancer Research Program, the NIH/National Cancer Institute (CA123318; to N.T. Ueno), MD Anderson's Cancer Center Support Grant (R01CA123318 and P30CA016672, used the Characterized Cell Line Core Facility, and Flow Cytometry and Cellular Imaging Facility), Syndax Pharmaceuticals, Inc., and EMD Serono, Inc.
Publisher Copyright:
©2017 AACR.
PY - 2017/8/15
Y1 - 2017/8/15
N2 - 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 proapoptotic NOXA. These are known to stabilize and degrade, respectively, MCL1, an antiapoptotic 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.
AB - 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 proapoptotic NOXA. These are known to stabilize and degrade, respectively, MCL1, an antiapoptotic 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.
UR - http://www.scopus.com/inward/record.url?scp=85028055678&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85028055678&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-16-2622
DO - 10.1158/1078-0432.CCR-16-2622
M3 - Article
C2 - 28465444
AN - SCOPUS:85028055678
SN - 1078-0432
VL - 23
SP - 4780
EP - 4792
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -