Abstract B34: Novel synergistic combination therapies with BET bromodomain inhibitors in triple-negative breast cancer

Samantha M. Bevill, N. Sciaky, B. Golitz, N. Rashid, J. Zawistowski, G. Johnson
{"title":"Abstract B34: Novel synergistic combination therapies with BET bromodomain inhibitors in triple-negative breast cancer","authors":"Samantha M. Bevill, N. Sciaky, B. Golitz, N. Rashid, J. Zawistowski, G. Johnson","doi":"10.1158/1557-3125.ADVBC17-B34","DOIUrl":null,"url":null,"abstract":"Adaptive resistance to targeted cancer therapies is a universal problem in cancer treatment where tumor cells circumvent targeted pathway inhibition to reactivate growth signaling. In our previous work, we observed genome-wide enhancer remodeling following MEK inhibition (MEKi) capable of driving adaptive gene transcription in triple-negative breast cancer (TNBC). Adaptive enhancers were enriched for the BET bromodomain protein BRD4 and cotreatment with MEKi and BET inhibitor (JQ1) could durably suppress TNBC growth in multiple cell lines and preclinical mouse models. There are currently 10 BET inhibitors in clinical trials being tested as single agents across multiple tumor types including TNBC. There is also a growing body of preclinical literature using epigenetic inhibitors to block the adaptive ability of tumor cells in combination with multiple targeted therapies. This led us to screen for inhibitors that synergize with JQ1 to suppress growth of TNBC using a 176-compound library enriched for epigenetic and kinase inhibitors. We performed synergy screens in 6 TNBC cell lines across 6 doses of JQ1 and each library compound. Using the Bliss Independence model to assess synergy, we found that inhibition of MEK, CDK9, Aurora Kinase, CREBBP/P300, and BAZ2A/B was strongly synergistic with JQ1. BRD4, CDK9, and the acetyltransferase CREBBP/P300 are all members of the P-TEFb transcriptional elongation complex. When we performed additional synergy screens against the P300 bromodomain inhibitor CPI-637, we found a significant overlap in synergistic targets with the JQ1 screen including MEK, BET bromodomain proteins, ERK, Aurora Kinase, and CDK9. BAZ2A/B inhibition using the small-molecule inhibitor GSK2801, which targets the bromodomain of BAZ2A/B, synergized significantly stronger with JQ1 across all cell lines compared to CPI637. BAZ2A/B proteins are members of nucleosome remodeling complexes that mediate DNA silencing by aiding in recruitment of histone modifying enzymes. Ongoing studies seek to understand the role of BAZ2A/B and the mechanism of GSK2801 synergy with BET bromodomain inhibition using RNA sequencing and ChIP sequencing experiments. These results define novel targets that synergize with JQ1 to suppress tumor cell growth and illuminate additional mechanisms of transcriptional regulation driven by BET bromodomain proteins in TNBC. Citation Format: Samantha M. Bevill, Noah Sciaky, Brian T. Golitz, Naim U. Rashid, Jon S. Zawistowski, Gary L. Johnson. Novel synergistic combination therapies with BET bromodomain inhibitors in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B34.","PeriodicalId":20897,"journal":{"name":"Resistance Mechanisms","volume":"27 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Resistance Mechanisms","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1158/1557-3125.ADVBC17-B34","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Adaptive resistance to targeted cancer therapies is a universal problem in cancer treatment where tumor cells circumvent targeted pathway inhibition to reactivate growth signaling. In our previous work, we observed genome-wide enhancer remodeling following MEK inhibition (MEKi) capable of driving adaptive gene transcription in triple-negative breast cancer (TNBC). Adaptive enhancers were enriched for the BET bromodomain protein BRD4 and cotreatment with MEKi and BET inhibitor (JQ1) could durably suppress TNBC growth in multiple cell lines and preclinical mouse models. There are currently 10 BET inhibitors in clinical trials being tested as single agents across multiple tumor types including TNBC. There is also a growing body of preclinical literature using epigenetic inhibitors to block the adaptive ability of tumor cells in combination with multiple targeted therapies. This led us to screen for inhibitors that synergize with JQ1 to suppress growth of TNBC using a 176-compound library enriched for epigenetic and kinase inhibitors. We performed synergy screens in 6 TNBC cell lines across 6 doses of JQ1 and each library compound. Using the Bliss Independence model to assess synergy, we found that inhibition of MEK, CDK9, Aurora Kinase, CREBBP/P300, and BAZ2A/B was strongly synergistic with JQ1. BRD4, CDK9, and the acetyltransferase CREBBP/P300 are all members of the P-TEFb transcriptional elongation complex. When we performed additional synergy screens against the P300 bromodomain inhibitor CPI-637, we found a significant overlap in synergistic targets with the JQ1 screen including MEK, BET bromodomain proteins, ERK, Aurora Kinase, and CDK9. BAZ2A/B inhibition using the small-molecule inhibitor GSK2801, which targets the bromodomain of BAZ2A/B, synergized significantly stronger with JQ1 across all cell lines compared to CPI637. BAZ2A/B proteins are members of nucleosome remodeling complexes that mediate DNA silencing by aiding in recruitment of histone modifying enzymes. Ongoing studies seek to understand the role of BAZ2A/B and the mechanism of GSK2801 synergy with BET bromodomain inhibition using RNA sequencing and ChIP sequencing experiments. These results define novel targets that synergize with JQ1 to suppress tumor cell growth and illuminate additional mechanisms of transcriptional regulation driven by BET bromodomain proteins in TNBC. Citation Format: Samantha M. Bevill, Noah Sciaky, Brian T. Golitz, Naim U. Rashid, Jon S. Zawistowski, Gary L. Johnson. Novel synergistic combination therapies with BET bromodomain inhibitors in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B34.
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
B34: BET溴结构域抑制剂联合治疗三阴性乳腺癌的新协同疗法
靶向癌症治疗的适应性耐药是癌症治疗中的一个普遍问题,肿瘤细胞绕过靶向途径抑制来重新激活生长信号。在我们之前的工作中,我们观察到三阴性乳腺癌(TNBC)中MEK抑制(MEKi)后的全基因组增强子重塑能够驱动适应性基因转录。在多种细胞系和临床前小鼠模型中,与MEKi和BET抑制剂(JQ1)共处理的适应性增强子富集了BET溴结构域蛋白BRD4,可以持久抑制TNBC的生长。目前有10种BET抑制剂正在临床试验中作为单一药物治疗多种肿瘤类型,包括TNBC。也有越来越多的临床前文献使用表观遗传抑制剂来阻断肿瘤细胞的适应能力,并结合多种靶向治疗。这促使我们筛选与JQ1协同抑制TNBC生长的抑制剂,使用一个富含表观遗传和激酶抑制剂的176个化合物文库。我们在6个TNBC细胞系中进行了6个剂量的JQ1和每个文库化合物的协同筛选。利用Bliss独立模型评估协同作用,我们发现MEK、CDK9、极光激酶、CREBBP/P300和BAZ2A/B的抑制与JQ1具有很强的协同作用。BRD4、CDK9和乙酰转移酶CREBBP/P300都是P-TEFb转录延伸复合物的成员。当我们对P300溴结构域抑制剂pci -637进行额外的协同筛选时,我们发现与JQ1筛选的协同靶点有显著的重叠,包括MEK、BET溴结构域蛋白、ERK、极光激酶和CDK9。使用靶向BAZ2A/B溴域的小分子抑制剂GSK2801抑制BAZ2A/B,与CPI637相比,在所有细胞系中与JQ1的协同作用明显更强。BAZ2A/B蛋白是核小体重塑复合体的成员,通过帮助募集组蛋白修饰酶介导DNA沉默。正在进行的研究试图通过RNA测序和ChIP测序实验了解BAZ2A/B的作用以及GSK2801协同BET溴域抑制的机制。这些结果确定了与JQ1协同抑制肿瘤细胞生长的新靶点,并阐明了TNBC中BET溴结构域蛋白驱动的转录调控的其他机制。引文格式:Samantha M. Bevill, Noah Sciaky, Brian T. Golitz, Naim U. Rashid, Jon S. Zawistowski, Gary L. Johnson。BET溴结构域抑制剂治疗三阴性乳腺癌的新型协同联合疗法[摘要]。摘自:AACR特别会议论文集:乳腺癌研究进展;2017年10月7-10日;费城(PA): AACR;癌症学报,2018;16(8 -增刊):摘要nr B34。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
Abstract B36: Progesterone receptor signaling in estrogen receptor-positive breast cancer Abstract A45: Kinome rewiring reveals AURKA is a molecular barrier to the efficacy of PI3K/mTOR-pathway inhibitors in breast cancer Abstract B34: Novel synergistic combination therapies with BET bromodomain inhibitors in triple-negative breast cancer Abstract A47: Long-term treatment of bortezomib reduced resistance to doxorubicin by reducing CerS6/GCS and elevating CerS2/GBA expressions Abstract A46: KLF4 overcomes tamoxifen resistance by suppressing MAPK signaling pathway in breast cancer
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1