PRISM Technology and Method

High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines

First publication of the PRISM method from 2016. 102 cell lines were labeled with unique 24-nucleotide barcodes and used to screen 8400 compounds. BRD-7880 was identified as a potent and highly specific inhibitor of aurora kinases B and C.

Yu C, et al. Nature Biotechnology, 2016.

Discovering the anticancer potential of non-oncology drugs by systematic viability profiling

An updated panel of 578 barcoded cancer cell lines were used to profile the activity of 4518 existing drugs with a diversity of indications. An unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines. Results were used to begin the PRISM drug repurposing resource (

Corsello SM, et al. Nature Cancer, 2020.

PRISM as a Drug Discovery Platform

INK4 Tumor Suppressor Proteins Mediate Resistance to CDK4/6 Kinase Inhibitors

Results from a standard PRISM assay using the PR1000 cell set showed INK4 overexpression (along with RB1 loss) to be among the top genomic alterations associated with resistance to CDK4/6 inhibition with Palbociclib. This paper also identified a new strategy to enhance inhibition of CDK4/6 kinases.

Li Q, et al. Cancer Discovery, 2022.

Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism

Results from a standard PRISM assay using the PR500 cell set suggested that the novel compound, XL177A, acts by USP7 inhibition and that sensitivity to USP7 inhibition is associated with the mutational status of TP53. This study also found two pediatric cancers, Ewing sarcoma, and malignant rhabdoid tumor, were sensitive to XL177A.

Schauer NJ, et al. Scientific Reports, 2020.

Acute pharmacological degradation of ERK5 does not inhibit cellular immune response or proliferation

Collaborators in the Gray lab at Stanford developed INY-06-061, a potent and selective heterobifunctional degrader of ERK5 to be used as a tool for validating phenotypes associated with ERK5 ablation. Results from a standard PRISM assay using the PR800 cell set verified a lack of dependency on ERK5 expression for cell growth (as no cell lines were sensitive to INY-06-061 treatment).

You I, et al. Cell Chemical Biology, 2022.

Novel PRISM Applications

Massively parallel pooled screening reveals genomic determinants of nanoparticle delivery

This paper introduces a novel ‘nanoPRISM’ method that leverages the PRISM cell set to understand the structure-function relationship of nanoparticles. For this study, the PR500 was treated with a library of modular fluorescent nanoparticles to understand regulators of nanoparticle delivery. In particular, SLC46A3 (a lysosomal transporter) was identified as a negative regulator of lipid-based nanoparticle uptake.

Boehnke N & Straehla JP, et al. Science, 2022.

A metastasis map of human cancer cell lines

This work details the creation of a first-generation metastasis map to reveal organ-specific patterns of metastasis of 500 PRISM cell lines. This was done by injecting pools of 5 cell lines into mouse xenograft models. Results were used to develop the MetMap resource (

Jin X, et al. Nature, 2020.

Methionine synthase is essential for cancer cell proliferation in physiological folate environments

The PR500 PRISM cell set was grown with either folic acid or 5-methyl tetrahydrofolate (THF) as a folate source and treated with several methotrexate doses. Cells exposed to 5-methyl THF were found to be more resistant to methotrexate indicating that environmental folate source affects folate metabolism and response to antifolate drugs.

Sullivan MR, et al. Nature Metabolism, 2021.

An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence

A panel of 253 PRISM cell lines were cultured in 2D and 3D conditions for 15 days with chemotherapy treatment. 3D cultures retained >10% viability whereas 2D cultures fell to <0.1%. Overall this study showed that CDK9 inhibition enhances chemosensitivity in Myc-suppressed, chemo-persistent cells.

Dhimolea E, et al. Cancer Cell, 2021.

Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity

198 PRISM cell lines were pooled and profiled by scRNAseq with the 10X Genomics Chromium system. This work compiled the landscape of heterogeneity across cancer cell lines and identified recurrent programs of cellular heterogeneity shared between tumors and certain cell lines.

Kinker GS, et al. Nature Genetics, 2020.

The landscape of cancer cell line metabolism

This work sought to create a  comprehensive resource of the metabolic diversity of cancer. Part of the study involved pooling 544 adherent PRISM cell lines which were then grown under media conditions with varied amino acid concentration to understand the effect on cell viability.

Li H, et al. Nature Medicine, 2019.

Multiplexed single-cell transcriptional response profiling to define cancer vulnerabilities and therapeutic mechanism of action

This paper introduces the MIX-Seq method for multiplexed transcriptional profiling of pooled cell lines that undergo drug treatment. Individual cell line identities were determined based on their single-nucleotide polymorphism (SNP) profiles. This method enables profiling of chemical or genetic perturbation response in pools of 100+ cancer cell lines.

McFarland JM, et al. Nature Communications, 2020.

Mitochondrial metabolism promotes adaptation to proteotoxic stress

This study was focused on understanding the mechanism cells use to adapt to proteotoxic stress. Part of the work used a panel of 549 PRISM cell lines grown in either glucose or galactose (to increase dependency on mitochondrial metabolism) in the presence or absence of bortezomib. Increased mitochondrial metabolism promoted proteasome inhibitor resistance.

Tsvetkov P, et al. Nature Chemical Biology, 2019.

PRISM in the Press

Anticancer Activity Discovered in Dozens of Existing Noncancer Drugs

Genetic Engineering & Biotechnology News, 22 Jan. 2020.

Could a drug for arthritis in dogs also fight cancer in people?

The Boston Globe, 20 Jan. 2020.

Dozens of non-oncology drugs can kill cancer cells

The Broad Institute, 20 Jan. 2020.

Old Drug, New Tricks: Existing Medicines Show Promise in Fighting Cancer

Scientific American, 20 Jan. 2020.

Conference Abstracts