High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines
Open accessAbstract
Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo.
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Mining correlations between cytotoxicity of 4,518 clinical and preclinical small molecules and E3 ligase expression across hundreds of cancer cell lines identified CR8, a CDK inhibitor, as a molecular glue degrader.
“Through systematic mining of databases for correlations between the cytotoxicity of 4,518 clinical and pre-clinical small molecules and E3 ligase expression levels across hundreds of human cancer cell lines,3–5 we identified CR8, a cyclin-dependent kinase (CDK) inhibitor,6 as a compound that acts as a molecular glue degrader.”
From The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K (2020) · cites this paper as [3]
The Abstract (page unavailable) describes correlating compound sensitivity with gene expression across cancer cell lines, supporting the database-mining approach attributed to this source. But this paper reports screening 8,400 compounds in 102 lines, not 4,518 compounds across hundreds of lines, and the cited passages do not identify E3 ligase expression as the correlate. The sentence presents CR8's identification as the citing authors’ own finding, not this source’s. (LLM, conf=0.84)
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- Authors
- Yu, C., Mannan, A. M., Yvone, G. M., Ross, K. N., Zhang, Y.-L., Marton, M. A., Taylor, B. R., Crenshaw, A., Gould, J. Z., Tamayo, P., Weir, B. A., Tsherniak, A., Wong, B., Garraway, L. A., Shamji, A. F., Palmer, M. A., Foley, M. A., Winckler, W., Schreiber, S. L., Kung, A. L., & Golub, T. R.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Corresponding author
- Golub, Todd R
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2016-02-29
- Volume
- 34
- Issue
- 4
- Pages
- 419-423
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC5508574
- OpenAlex
- W2294990791
- Semantic Scholar
- d59fcb6213f2a487d74622eba3e7e935247a737a
- Cited by
- 362
- References
- 27
- Citations by year
- 2026: 26 · 2025: 48 · 2024: 50 · 2023: 62 · 2022: 46 · 2021: 44 · 2020: 35 · 2019: 24 · 2018: 9 · 2017: 14 · 2016: 4
- FWCI
- 7.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Prostate Cancer Foundation
- Conquer Cancer Foundation
- National Institutes of Health
- National Human Genome Research Institute (RL1HG004671)
- National Cancer Institute (RL1CA133834, U54CA112962)
- National Institute of General Medical Sciences (RL1GM084437)
- National Institute of Dental and Craniofacial Research (UL1DE019585)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- PRISM, compound screening, Aurora kinase inhibitors, xenograft tumor formation, cancer cell lines
- MeSH terms
- Animals, Humans, Neoplasms, Drug Resistance, Neoplasm, Cell Line, Tumor, Mice, DNA Barcoding, Taxonomic, High-Throughput Nucleotide Sequencing, Genotyping Techniques
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