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  2. 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

  • Commun Biol. 2021 Mar 25;4(1):399. doi: 10.1038/s42003-021-01929-1.
Yosi Gilad 1 Yossi Eliaz 2 Yang Yu 1 Adam M Dean 1 San Jung Han 1 Li Qin 1 Bert W O'Malley 3 David M Lonard 4
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
  • 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. berto@bcm.edu.
  • 4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. dlonard@bcm.edu.
Abstract

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.

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