CRISPR screen identifies GATAD1 as a synthetic lethal target with CDK4/6 inhibitors in estrogen receptor-positive breast cancer.

Estrogen receptor-positive (ER+) breast cancer represents approximately two-thirds of all breast cancers and has a sustained risk of late disease recurrence. Combining cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with anti-estrogen therapies significantly improves ER+ advanced breast cancer clinical outcomes. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited their success. We used CRISPR to screen MCF-7 cells to explore the targets whose inhibition is synthetic lethal with CDK4/6 inhibitors in ER+ breast cancer cells. We found that GATA zinc finger domain containing 1 (GATAD1) is a new synthetic lethal target with CDK4/6 inhibitors in ER+ breast cancer cells. Mechanistically, GATAD1 promotes cell proliferation by transcriptionally inhibiting p21 in ER+ breast cancer cells. GATAD1 depletion decreased the phosphorylation of CDK2/4 and RB transcriptional corepressor 1 (RB1), inducing cell cycle arrest. P21 overexpression abolished the enhanced proliferation induced by GATAD1 overexpression. Our results identify GATAD1 as a therapeutic target in ER+ breast cancer, which is beneficial to provide a novel treatment strategy. © 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Citation

Wenqiang Liu, Ruhua Zhang, Xinhao Yu, Yu Zhang, Tiebang Kang, Dan Liao. CRISPR screen identifies GATAD1 as a synthetic lethal target with CDK4/6 inhibitors in estrogen receptor-positive breast cancer. Medical oncology (Northwood, London, England). 2023 Aug 11;40(9):267

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PMID: 37567972

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