Related Experiment Video
Updated: Mar 31, 2026
Drug-induced Sensitization of Adenylyl Cyclase: Assay Streamlining and Miniaturization for Small Molecule and siRNA Screening Applications
Published on: January 27, 2014
Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset
Brinton Seashore-Ludlow1, Matthew G Rees1, Jaime H Cheah1
1Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
Unlabelled:
Identifying genetic alterations that prime a cancer cell to respond to a particular therapeutic agent can facilitate the development of precision cancer medicines. Cancer cell-line (CCL) profiling of small-molecule sensitivity has emerged as an unbiased method to assess the relationships between genetic or cellular features of CCLs and small-molecule response. Here, we developed annotated cluster multidimensional enrichment analysis to explore the associations between groups of small molecules and groups of CCLs in a new, quantitative sensitivity dataset. This analysis reveals insights into small-molecule mechanisms of action, and genomic features that associate with CCL response to small-molecule treatment. We are able to recapitulate known relationships between FDA-approved therapies and cancer dependencies and to uncover new relationships, including for KRAS-mutant cancers and neuroblastoma. To enable the cancer community to explore these data, and to generate novel hypotheses, we created an updated version of the Cancer Therapeutic Response Portal (CTRP v2).
Significance:
We present the largest CCL sensitivity dataset yet available, and an analysis method integrating information from multiple CCLs and multiple small molecules to identify CCL response predictors robustly. We updated the CTRP to enable the cancer research community to leverage these data and analyses.
Insights
Researchers identified genetic features linked to cancer cell drug response using a large dataset and new analysis methods. This work advances precision medicine by uncovering new therapeutic targets and updating the Cancer Therapeutic Response Portal.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Precision cancer medicine relies on identifying genetic alterations that predict therapeutic response.
- Cancer cell-line (CCL) profiling offers an unbiased approach to link CCL features with drug sensitivity.
Purpose of the Study:
- To explore associations between small molecules and CCLs using a quantitative sensitivity dataset.
- To uncover mechanisms of action and genomic features correlating with CCL drug response.
Main Methods:
- Developed annotated cluster multidimensional enrichment analysis.
- Analyzed a new, large quantitative sensitivity dataset of cancer cell lines and small molecules.
- Updated the Cancer Therapeutic Response Portal (CTRP v2).
Main Results:
- Recapitulated known drug-response relationships and identified novel ones.
- Discovered new associations for KRAS-mutant cancers and neuroblastoma.
- Revealed insights into small-molecule mechanisms and predictive genomic features.
Conclusions:
- Presented the largest CCL sensitivity dataset to date.
- Developed a robust analysis method for identifying drug response predictors.
- Enhanced the CTRP to facilitate cancer research and hypothesis generation.
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