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CRISPR library screening analysis on DMSO and Erlotinib 10µM treated samples

ABSTRACT: CRISPR library screening analysis on DMSO and Erlotinib 10µM treated samples

PROVIDER: PRJNA1174095 | ENA |

REPOSITORIES: ENA

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CRISPR library screening analysis on DMSO and Erlotinib 10µM treated samples

Project description:Triple-negative breast cancers (TNBCs) are the most aggressive subtype of breast cancer that have poor prognosis and very few treatment options. Although approximately 40-70% of TNBC patients have EGFR overexpression, anti-EGFR therapies exerted little to no clinical benefit. This could be due to (i) the presence of an inherent resistance mechanism, (ii) the presence of EGFR protein in its inactive form, or (iii) lack of EGFR on the surface of plasma membrane. Several studies have shown that EGFR is present in the intracellular compartments, instead of the plasma membrane surface, in TNBC patients. Previous studies have demonstrated that intracellular EGFR renders TNBC tumors resistant to anti-EGFR therapies. Here, we used genome wide CRISPR library screening to identify the markers of resistance to EGFR inhibitors. Our CRISPR screening identified a redox protein, thioredoxin reductase 3 (TXNRD3), to be depleted in erlotinib-treated MDA-MB-231 cells suggesting that loss of TXNRD3 may sensitize TNBC cells to EGFR inhibitors. siRNA-induced knockdown and pharmacological inhibition of TXNRD3 using an FDA-approved drug auranofin significantly sensitized EGFR-high TNBC cells to EGFR inhibitors. Mechanistically, TXNRD3 knockdown or inhibition increased oxidative stress resulting in increased EGFR phosphorylation at Y1068 (active EGFR protein). Moreover, auranofin also increased surface accumulation of EGFR and sensitized SUM159PT cells to cetuximab-induced ADCC. Auranofin and erlotinib combination therapy exerted a significant anti-cancer activity in vivo in MDA-MB-231 cell line-derived xenograft and in murine syngeneic 4T1.2 TNBC model. Collectively, these data suggests that TXNRD3 inhibition using auranofin activates EGFR and increases its surface localization, which then sensitizes TNBC cells to anti-EGFR therapies. Hence, auranofin combined with anti-EGFR therapies may be a viable approach for the treatment of TNBC patients.

2025-09-01 | GSE279690 | GEO

Genome-scale CRISPR screening identifies cell cycle and protein ubiquitination processes as druggable targets for erlotinib-resistant lung cancer

Project description:This study aims to identify new genes and pathways associated with erlotinib sensitivity in order to develop novel therapeutic strategies. Here, we induced artificial knock-out (KO) mutations in erlotinib-resistant human lung cancer cells (NCI-H820) using a genome-scale CRISPR-Cas9 sgRNA library to screen for genes involved in erlotinib susceptibility.

2020-11-30 | GSE142669 | GEO

BT20_24hr_DMSOvERLOTINIB_RNAseq and WHOLE GENOME CRISPR screen

Project description:BT20 (TNBC) cells were cultured with either DMSO (v/v%) or Erlotinib (10uM) for 24 hours to observe differential expression changes between conditions. CAS-9 expressing BT20 (TNBC) cells were transduced with a whole-genome library of CRISPR sgRNAs; then, cultured them with either DMSO (v/v%) or Erlotinib (10uM) and collected samples to observe differential sgRNA abundances between conditions.

2020-11-01 | GSE148096 | GEO

Enabling multiplexed CRISPR/Cas9 screening via massively parallel in-library ligation

Project description:Here we developed a massively parallel in-library ligation methodology to simultaneously perturb four pre-designed targets in CRISPR/Cas9 screening. Thousands of pairs of sequences precisely ligated with their counterparts in library, which enabled simultaneous expression of four gRNAs from each single vector. We demonstrated this novel method with 6,236 4-gene combinations targeting 1,599 immune response related genes, and generated a plasmid library with 1,400x coverage. The library performance was evaluated in a canonical T cell activation experiment, and combinations involved in TCR signaling pathway or TCR complex were successfully identified as positive regulators. Novel combination that is reflecting a potential pathway crosstalk was also verified. This new methodology expands the capacity of the perturbation in CRISPR screening and provided a powerful tool for researches in broad fields to study the combinatorial outcomes from coordinated gene behaviors.

2022-06-15 | GSE149945 | GEO

Gene expression analysis in EGFR-mutant NSCLC cells treated with erlotinib versus DMSO

Project description:This experiment is designed to detect genes differentially expressed in 2uM erlotinib treatment versus DMSO treatment and to identify differential gene set enrichments.

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CRISPR Screening in Glioblastoma

Project description:This is an in vitro genome-wide CRISPR/cas9 screen in human glioblastoma stem cells, screening for genes essential for survival of these cells. These cells express cas9 and have been transfected with a guide RNA library causing gene knockouts. We will analyse the sequencing data for depletion of guide RNAs. In this particular study, we will do RNA sequencing to correlate CRISPR with expression levels in specific cancer cell subpopulations. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

2016-03-22 | E-ERAD-448 | biostudies-arrayexpress

A CRISPR/Cas9 library screening identified CARM1 as a critical inhibitor for Sorafenib-induced ferroptosis in hepatocellular carcinoma cells [CRISPR screen]

Project description:To find epigenetic factors potentially involved in Sorafenib resistance in hepatocellular carcinoma cells, an epigenetic factors-targeted CRISPR/Cas9 library was applied to perform the screening.

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Enabling multiplexed CRISPR/Cas9 screening via massively parallel in-library ligation

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Rapid CRISPR/Cas12a-based dual-crRNA library screening in high fidelity reveals novel genetic interactions during hepatocarcinogenesis [library seq]

Project description:CRISPR/Cas12a-based combinational screening has shown remarkable potential in identifying genetic interactions. Here, we described an innovative method for combinational genetic screen with rapid constructing of dual-crRNA library by gene splicing through overlap extension PCR (SOE PCR) and the adoption of CeCas12a, which was identified previously by us with strict PAM recognition and low off- targeting, to guarantee the fidelity and efficiency. The custom, pooled SOE crRNA array (SOCA) library for double knockout screen could be conveniently constructed in lab for widespread use and CeCas12a mediated high fidelity screen display good performances even under negative selection screen. By designing an SOCA dual-crRNA library which covered the most of kinase and metabolism-associated gene targets of FDA- approved drugs that were implicated in hepatocellular carcinoma (HCC) tumorigenesis, novel cross talks between the two gene sets were negatively selected out to synergistically inhibit HCC cell growth in vitro and in vivo and also validated by virtual double knockdown screening based on TCGA databases. Thus through our rapid, efficient and high fidelity double knockout screening system, it is very promising to systemically dig genetic interactions between multiple gene sets or synergistic combinations of FDA-approved drugs for clinical translational medicine in the future.

2024-08-02 | GSE236821 | GEO

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