PRISM: A Novel Bead-Based Biological Barcode Assay

Enabling large-scale screening of small-molecule libraries in pooled cancer cell lines to discover genotype-specific vulnerabilities

Barcoding is no longer confined to the black stripes of the ubiquitous Universal Product Code (UPC) label found on nearly every product we purchase. Conservationist Paul Hebert was the first to demonstrate the feasibility and utility of DNA barcoding as a way to identify species in 2003.

Applications outside the research lab include the detection of food fraud, where lower quality fish is substituted for a more desirable species. A recent study by OCEANA found that 39 percent of 142 seafood samples collected and DNA tested from grocery stores, restaurants, and sushi venues in New York City were mislabeled.

While DNA barcoding has already empowered single-cell analysis, Todd Golub’s team at the Broad Institute developed a new method to speed oncology drug discovery. Profiling Relative Inhibition Simultaneously in Mixtures (PRISM), recently reported in the journal Nature Biotechnology, relies on 24 nucleotide long biological barcodes that are stably integrated into genetically distinct tumor cell lines. “We wanted an approach to screen cancer cell lines that both recognized their complexity and allowed us to scale our studies,” said Dr. Chris Mader, Senior Group Leader, PRISM Project.

PRISM provides a practical solution for screening drug candidate compounds against a large number of cancer cell lines. While cancer is inherently genetically diverse, methods limitations have historically limited the number of cell lines that researchers use to develop new drugs. This breakthrough method allows for the simultaneous interrogation of multiple cell lines. In brief, cells are barcoded, pooled, and then treated with a drug. Genomic DNA is isolated from surviving cells, hybridized to Luminex® microspheres and then identified and quantified with a FLEXMAP 3D® instrument.

Golub’s team validated the PRISM assay in vitro and in vivo and found that it:

  • Performs as intended, distinguishing genotype-specific drug responses in lung cancer cell lines
  • Detects the vast majority of cell lines from a single xenograft
  • Accurately assesses drug sensitivity in wild-type and mutant cell lines
  • Is suitable for drug discovery, specifically library screening applications
  • Generates hypotheses about the mechanism of action and molecular target of unknown candidate compounds, based on activity pattern across multiple cell lines compared to reference libraries of compounds

Now that the Golub lab has demonstrated proof of concept with PRISM, Mader explains, “We are working to industrialize the process to enable cell profiling at the earliest stage of drug discovery in an effort to rapidly find new opportunities for cancer therapeutics.”

PRISM: A Novel Bead-Based Biological Barcode Assay Infographic - A Novel Method for Profiling Drug Candidates Across Large Number of Pooled Cell Lines

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