MCL1
三阴性乳腺癌
癌症研究
组蛋白脱乙酰酶抑制剂
炎症性乳腺癌
组蛋白脱乙酰基酶
乳腺癌
癌症
联合疗法
表观遗传疗法
靶向治疗
医学
药理学
生物
内科学
下调和上调
组蛋白
基因表达
DNA甲基化
基因
生物化学
作者
Angie M. Torres-Adorno,Jangsoon Lee,Takahiro Kogawa,Peter Ordentlich,Debu Tripathy,Bora Lim,Naoto T. Ueno
标识
DOI:10.1158/1078-0432.ccr-16-2622
摘要
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 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. Clin Cancer Res; 23(16); 4780–92. ©2017 AACR.
科研通智能强力驱动
Strongly Powered by AbleSci AI