ArticleMolecular systems biology2020
Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens.
Article in Molecular systems biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
59 citing papers in PubMed, 1 synthesis or guideline pooled it, 110 citations in OpenAlex.
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- DR.DEGMON: self-explainable deep neural network for drug-induced cell viability prediction incorporating differentially expressed genes and gene ontology.BMC medical genomics · 2026Article
- Drug response profile-based machine learning enables strategic cell line and compound selection for drug development.Bioinformatics (Oxford, England) · 2026Article
- Using cancer profiles to identify synthetic lethal therapeutic targets and predictive biomarkers in cancer gene dependency data.Bioinformatics (Oxford, England) · 2026Article
- CRISPR screening redefines therapeutic target identification and drug discovery with precision and scalability.Journal of pharmaceutical analysis · 2026Review
- Multi-omic integration identifies broad drug resistance mechanisms and strategies to therapeutically reprogram cancer cells.iScience · 2026Article
- CRISPR-Edited Cell Lines: A New Era in Functional Oncology Research.Current pharmaceutical design · 2026Review
- Synthetic lethality in cancer drug discovery: challenges and opportunities.Nature reviews. Drug discovery · 2026Review
- Challenges and opportunities for oncology drug repurposing informed by synthetic lethality.NPJ systems biology and applications · 2025Article
- Targeting Pan-Cancer Stemness: Core Regulatory lncRNAs as Novel Therapeutic Vulnerabilities.International journal of molecular sciences · 2025Article
- A human metabolic map of pharmacological perturbations reveals drug modes of action.Nature biotechnology · 2025Article
- DeepTarget predicts anti-cancer mechanisms of action of small molecules by integrating drug and genetic screens.NPJ precision oncology · 2025Article
- AI-Driven Polypharmacology in Small-Molecule Drug Discovery.International journal of molecular sciences · 2025Review
- The synthetic lethal interaction between CDS1 and CDS2 is a vulnerability in uveal melanoma and across multiple tumor types.Nature genetics · 2025Article
- Finding a needle in a haystack: functional screening for novel targets in cancer immunology and immunotherapies.Oncogene · 2025Review
- Article
- EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma.Neuro-oncology · 2025Article
- Combining Oligo Pools and Golden Gate Cloning to Create Protein Variant Libraries or Guide RNA Libraries for CRISPR Applications.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Synthetic augmentation of cancer cell line multi-omic datasets using unsupervised deep learning.Nature communications · 2024Article
- High TNF and NF-κB Pathway Dependency Are Associated with AZD5582 Sensitivity in OSCC via CASP8-Dependent Apoptosis.Cancer research communications · 2024Article
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Authors and funding
28 authors at 4 institutions in 3 countries.
Funding
Abstract
Low success rates during drug development are due, in part, to the difficulty of defining drug mechanism-of-action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug sensitivity measurements for 397 unique anti-cancer drugs with genome-wide CRISPR loss-of-function screens in 484 cell lines to systematically investigate cellular drug mechanism-of-action. We observed an enrichment for positive associations between the profile of drug sensitivity and knockout of a drug's nominal target, and by leveraging protein-protein networks, we identified pathways underpinning drug sensitivity. This revealed an unappreciated positive association between mitochondrial E3 ubiquitin-protein ligase MARCH5 dependency and sensitivity to MCL1 inhibitors in breast cancer cell lines. We also estimated drug on-target and off-target activity, informing on specificity, potency and toxicity. Linking drug and gene dependency together with genomic data sets uncovered contexts in which molecular networks when perturbed mediate cancer cell loss-of-fitness and thereby provide independent and orthogonal evidence of biomarkers for drug development. This study illustrates how integrating cell line drug sensitivity with CRISPR loss-of-function screens can elucidate mechanism-of-action to advance drug development.
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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.