A genome-scale CRISPR Cas9 dropout screen identifies synthetically lethal targets in SRC-3 inhibited cancer cells.
A genome-scale CRISPR Cas9 dropout screen identifies synthetically lethal targets in SRC-3 inhibited cancer cells.
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DOI：
10.1038/s42003-021-01929-1
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发表时间：
2021-03-25
影响因子：
5.9
通讯作者：
Lonard DM
中科院分区：
文献类型：
--
作者：
Gilad Y;Eliaz Y;Yu Y;Dean AM;Han SJ;Qin L;O'Malley BW;Lonard DM
Steroid receptor coactivator 3 (SRC-3/NCoA3/AIB1), is a key regulator of gene transcription and it plays a central role in breast cancer (BC) tumorigenesis, making it a potential therapeutic target. Beyond its function as an important regulator of estrogen receptor transcriptional activity, SRC-3 also functions as a coactivator for a wide range of other transcription factors, suggesting SRC-3 inhibition can be beneficial in hormone-independent cancers as well. The recent discovery of a potent SRC-3 small molecule inhibitor, SI-2, enabled the further development of additional related compounds. SI-12 is an improved version of SI-2 that like SI-2 has anti-proliferative activity in various cancer types, including BC. Here, we sought to identify gene targets, that when inhibited in the presence of SI-12, would lead to enhanced BC cell cytotoxicity. We performed a genome-scale CRISPR-Cas9 screen in MCF-7 BC cells under conditions of pharmacological pressure with SI-12. A parallel screen was performed with an ER inhibitor, fulvestrant, to shed light on both common and distinct activities between SRC-3 and ERα inhibition. Bearing in mind the key role of SRC-3 in tumorigenesis of other types of cancer, we extended our study by validating potential hits identified from the MCF-7 screen in other cancer cell lines. Using a CRISPR-based large-scale screen, Gilad et al. identify the genes that show synthetic lethality with an SRC-3 inhibitor in breast cancer cells while contrasting this with the estrogen receptor degrader fulvestrant. This study provides insights into the development of therapeutic strategies for cancer forms that involve SRC-3.
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影响因子：
10.5
作者：
Dasgupta S;Lonard DM;O'Malley BW
通讯作者：
O'Malley BW
DOI：
10.1038/nrd.2016.238
发表时间：
2017-02
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Fellmann C;Gowen BG;Lin PC;Doudna JA;Corn JE
通讯作者：
Corn JE
CRISPR-CAS9介导的基因失活的高度活性SGRNA的合理设计。
影响因子：
46.9
作者：
Doench, John G.;Hartenian, Ella;Graham, Daniel B.;Tothova, Zuzana;Hegde, Mudra;Smith, Ian;Sullender, Meagan;Ebert, Benjamin L.;Xavier, Ramnik J.;Root, David E.
通讯作者：
Root, David E.
影响因子：
14.8
作者：
Drost J;Karthaus WR;Gao D;Driehuis E;Sawyers CL;Chen Y;Clevers H
通讯作者：
Clevers H
影响因子：
5.3
作者：
Amazit, Larbi;Pasini, Luigi;Mancini, Michael A.
通讯作者：
Mancini, Michael A.