ArticleJCI insight2021
A genome-wide CRISPR/Cas9 screen in acute myeloid leukemia cells identifies regulators of TAK-243 sensitivity.
Article in JCI insight, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 50 citations in OpenAlex.
- The ubiquitin-activating enzyme inhibitor TAK-243 activates store-operated CaBiochimica et biophysica acta. Molecular cell research · 2026Article
- Ubiquitin System-Driven Proteostasis in DNA Damage Response.International journal of molecular sciences · 2026Review
- Recent advances in drug delivery and treatment strategies for acute myeloid leukemia.International journal of pharmaceutics · 2025Review
- Impact of physiological media on acute myeloid leukemia bioenergetics and cell proliferation.Cancer & metabolism · 2025Article
- Genome-wide CRISPR/Cas9 screen identifies AraC-daunorubicin-etoposide response modulators associated with outcomes in pediatric AML.Blood advances · 2025Article
- Integrated Pan-Cancer Profiling and Breast Cancer Validation Identify BEND3 as a Potential Prognostic and Immune Biomarker.Breast cancer (Dove Medical Press) · 2025Article
- Combination screen in multi-cell type tumor spheroids reveals interaction between aryl hydrocarbon receptor antagonists and E1 ubiquitin-activating enzyme inhibitor.SLAS discovery : advancing life sciences R & D · 2024Article
- Genome-wide in vivo CRISPR screen identifies TGFβ3 as actionable biomarker of palbociclib resistance in triple negative breast cancer.Molecular cancer · 2024Article
- Function, mechanism and drug discovery of ubiquitin and ubiquitin-like modification with multiomics profiling for cancer therapy.Acta pharmaceutica Sinica. B · 2023Review
- Use of CRISPR-based screens to identify mechanisms of chemotherapy resistance.Cancer gene therapy · 2023Review
- Review
- CD24-associated ceRNA network reveals prognostic biomarkers in breast carcinoma.Scientific reports · 2023Article
- The human ATP-binding cassette (ABC) transporter superfamily.Human mutation · 2022Review
- Review
- CRISPR/Cas9 gene editing: a new approach for overcoming drug resistance in cancer.Cellular & molecular biology letters · 2022Review
- Targeting the Ubiquitin-Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Article
- Article
- Application of CRISPR-Cas9 System to Study Biological Barriers to Drug Delivery.Pharmaceutics · 2022Review
- GRP78 blockade overcomes intrinsic resistance to UBA1 inhibitor TAK-243 in glioblastoma.Cell death discovery · 2022Article
- ABCB1 limits the cytotoxic activity of TAK-243, an inhibitor of the ubiquitin-activating enzyme UBA1.Frontiers in bioscience (Landmark edition) · 2022Article
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
Abstract
TAK-243 is a first-in-class inhibitor of ubiquitin-like modifier activating enzyme 1 that catalyzes ubiquitin activation, the first step in the ubiquitylation cascade. Based on its preclinical efficacy and tolerability, TAK-243 has been advanced to phase I clinical trials in advanced malignancies. Nonetheless, the determinants of TAK-243 sensitivity remain largely unknown. Here, we conducted a genome-wide CRISPR/Cas9 knockout screen in acute myeloid leukemia (AML) cells in the presence of TAK-243 to identify genes essential for TAK-243 action. We identified BEN domain-containing protein 3 (BEND3), a transcriptional repressor and a regulator of chromatin organization, as the top gene whose knockout confers resistance to TAK-243 in vitro and in vivo. Knockout of BEND3 dampened TAK-243 effects on ubiquitylation, proteotoxic stress, and DNA damage response. BEND3 knockout upregulated the ATP-binding cassette efflux transporter breast cancer resistance protein (BCRP; ABCG2) and reduced the intracellular levelsof TAK-243. TAK-243 sensitivity correlated with BCRP expression in cancer cell lines of different origins. Moreover, chemical inhibition and genetic knockdown of BCRP sensitized intrinsically resistant high-BCRP cells to TAK-243. Thus, our data demonstrate that BEND3 regulates the expression of BCRP for which TAK-243 is a substrate. Moreover, BCRP expression could serve as a predictor of TAK-243 sensitivity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.