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DOI | 10.1038/s41467-018-03786-9 |
Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity | |
Soderquist, Ryan S.1; Crawford, Lorin2,3; Liu, Esther1; Lu, Min1; Agarwal, Anika1; Anderson, Grace R.1; Lin, Kevin H.1; Winter, Peter S.1; Cakir, Merve1; Wood, Kris C.1 | |
2018-08-29 | |
发表期刊 | NATURE COMMUNICATIONS |
ISSN | 2041-1723 |
出版年 | 2018 |
卷号 | 9 |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | While inhibitors of BCL-2 family proteins (BH3 mimetics) have shown promise as anti-cancer agents, the various dependencies or co-dependencies of diverse cancers on BCL-2 genes remain poorly understood. Here we develop a drug screening approach to define the sensitivity of cancer cells from ten tissue types to all possible combinations of selective BCL-2, BCL-X-L, and MCL-1 inhibitors and discover that most cell lines depend on at least one combination for survival. We demonstrate that expression levels of BCL-2 genes predict single mimetic sensitivity, whereas EMT status predicts synergistic dependence on BCL-X-L+MCL-1. Lastly, we use a CRISPR/Cas9 screen to discover that BFL-1 and BCL-w promote resistance to all tested combinations of BCL-2, BCL-X-L, and MCL-1 inhibitors. Together, these results provide a roadmap for rationally targeting BCL-2 family dependencies in diverse human cancers and motivate the development of selective BFL-1 and BCL-w inhibitors to overcome intrinsic resistance to BH3 mimetics. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000442998800018 |
WOS关键词 | ENDOPLASMIC-RETICULUM STRESS ; BH3-ONLY PROTEIN NOXA ; ACUTE MYELOID-LEUKEMIA ; SIGNALING PATHWAYS ; BREAST-CANCER ; CELL-DEATH ; INHIBITOR ; ABT-199 ; POTENT ; ASSOCIATION |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/203749 |
专题 | 资源环境科学 |
作者单位 | 1.Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA; 2.Duke Univ, Dept Stat, Durham, NC 27710 USA; 3.Brown Univ, Sch Publ Hlth, Dept Biostat, Providence, RI 02903 USA |
推荐引用方式 GB/T 7714 | Soderquist, Ryan S.,Crawford, Lorin,Liu, Esther,et al. Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity[J]. NATURE COMMUNICATIONS,2018,9. |
APA | Soderquist, Ryan S..,Crawford, Lorin.,Liu, Esther.,Lu, Min.,Agarwal, Anika.,...&Wood, Kris C..(2018).Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity.NATURE COMMUNICATIONS,9. |
MLA | Soderquist, Ryan S.,et al."Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity".NATURE COMMUNICATIONS 9(2018). |
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