期刊
CANCER DISCOVERY
卷 10, 期 9, 页码 1312-1329出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-19-1493
关键词
-
类别
资金
- Terry Fox Research Institute (New Frontiers Research Program) [PPG-1064]
- Canadian Cancer Research Society
- Ontario Institute for Cancer Research through Government of Ontario
- Canadian Institute for Health Research (CIHR) [136963, 158225, 363288]
- Princess Margaret Cancer Centre
- Princess Margaret Cancer Foundation
- Ontario Ministry of Health
- Reseau de Recherche en Cancer of the FRQS
- Quebec Breast Cancer Foundation
- Oncopole
- Gattuso-Slaight Personalized Cancer Medicine Fund at Princess Margaret Cancer Centre
- SU2C Canada -Canadian Cancer Society Breast Cancer Dream Team Research Funding [SU2C-AACR-DT-18-15]
- Government of Ontario
- CIHR
- Fonds de Recherche en Sante du Quebec (FRQS) postdoctoral research award
- Cancer Research Society Next-Generation of Scientists transition award
- Ontario Institute for Cancer Research
- CIHR New Investigator Award
- Bernard and Francine Dorval Award for Excellence from the Canadian Cancer Society
- Diane and Sal Guerra Chair in Cancer Genetics at McGill University
- CIHR fellowship
- Connaught International Scholarships
- FRQS
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada through Ontario Genomics Institute [OGI-055]
- Innovative Medicines Initiative (EU/EFPIA
- ULTRA-DD) [115766]
- Janssen
- Merck KGaA
- Darmstadt, Germany
- MSD
- Novartis Pharma AG
- Ontario Ministry of Research, Innovation and Science (MRIS)
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome
Tumor progression upon treatment arises from preexisting resistant cancer cells and/or adaptation of persister cancer cells committing to an expansion phase. Here, we show that evasion from viral mimicry response allows the growth of taxane-resistant triple-negative breast cancer (TNBC). This is enabled by an epigenetic state adapted to taxane-induced metabolic stress, where DNA hypomethylation over loci enriched in transposable elements (TE) is compensated by large chromatin domains of H3K27me3 to warrant TE repression. This epigenetic state creates a vulnerability to epigenetic therapy against EZH2, the H3K27me3 methyltransferase, which alleviates TE repression in taxane-resistant TNBC, leading to double-stranded RNA production and growth inhibition through viral mimicry response. Collectively, our results illustrate how epigenetic states over TEs promote cancer progression under treatment and can inform about vulnerabilities to epigenetic therapy. SIGNIFICANCE Drug-resistant cancer cells represent a major barrier to remission for patients with cancer. Here we show that drug-induced metabolic perturbation and epigenetic states enable evasion from the viral mimicry response induced by chemotherapy in TNBC. These epigenetic states define a vulnerability to epigenetic therapy using EZH2 inhibitors in taxane-resistant TNBC.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据