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A genome-wide in vivo CRISPR activation screen identifies BACE1 as a therapeutic vulnerability of lung cancer brain metastasis

ABSTRACT: A genome-wide in vivo CRISPR activation screen identifies BACE1 as a therapeutic vulnerability of lung cancer brain metastasis

PROVIDER: PRJNA994960 | ENA |

REPOSITORIES: ENA

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A genome-wide in vivo CRISPR activation screen identifies BACE1 as a therapeutic vulnerability of lung cancer brain metastasis

Project description:Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumor and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome-wide CRISPR activation (CRISPRa) screen to identify molecular drivers of brain metastasis from a NSCLC patient-derived xenograft model. We discovered activation of the Alzheimer’s disease associated -site amyloid precursor protein cleaving enzyme 1 (BACE1) led to a significant increase in brain metastasis. Furthermore, BACE1 knockout or inhibition with MK-8931 treatment blocked NSCLC brain metastasis. Mechanistically, we identified BACE1 cleaves an N-terminal fragment of EGFR to activate downstream signalling through MEK and ERK and drive this metastatic phenotype. Together our data highlights the power of in vivo CRISPR screening to unveil novel molecular drivers and potential therapeutic targets of NSCLC brain metastasis.

2025-07-04 | GSE237446 | GEO

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In vivo CRISPR/Cas9 screen to identify candidate therapeutic gene targets to enhance docetaxel efficacy in prostate cancer

Project description:Docetaxel chemotherapy in metastatic prostate cancer offers only a modest survival benefit due to emerging resistance. To identify candidate therapeutic gene targets, we applied a murine prostate cancer orthograft model that recapitulates clinical invasive prostate cancer in a genome-wide CRISPR/Cas9 screen under docetaxel treatment pressure.

2020-10-07 | E-MTAB-9482 | biostudies-arrayexpress

Genome-wide CRISPR-Cas9 screen reveals selective vulnerability of ARID1A deficiency Hepatocellular Carcinoma

Project description:Genome-wide CRISPR-Cas9 screen reveals selective vulnerability of ARID1A deficiency Hepatocellular Carcinoma

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CDK7 is a novel therapeutic vulnerability in Fibrolamellar cancer

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A chemical screen identifies PRMT5 as a therapeutic vulnerability for paclitaxel-resistant triple-negative breast cancer

Project description:Paclitaxel -resistant triple negative breast cancer (TNBC) remains one of the most challenging breast cancers to treat. Using an epigenetic chemical probe screen, we uncover an acquired vulnerability of paclitaxel-resistant TNBC cells to protein arginine methyltransferases (PRMTs) inhibition. Analysis of cell lines and in-house clinical samples demonstrates that resistant cells evade paclitaxel killing through stabilizing mitotic chromatin assembly. Genetic or pharmacologic inhibition of PRMT5 alters RNA splicing, particularly intron retention of Aurora kinases B (AURKB), leading to a decrease in protein expression, and finally results in selective mitosis catastrophe in paclitaxel-resistant cells. These findings are fully recapitulated in a patient derived xenograft (PDX) model generated from a paclitaxel-resistant TNBC patient, providing the rationale for targeting PRMTs in paclitaxel-resistant TNBC.

2024-06-21 | GSE264630 | GEO

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