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Multiparametric High-Content Cell Painting Identifies Copper Ionophores as Selective Modulators of Esophageal Cancer
Rebecca E Hughes1, Richard J R Elliott1, Xiaodun Li2
1Cancer Research UK Edinburgh Centre, Institute of Genetics & Cancer, The University of Edinburgh, Western General Hospital, Edinburgh EH4 2XR, U.K.
Abstract:
Esophageal adenocarcinoma is of increasing global concern due to increasing incidence, a lack of effective treatments, and poor prognosis. Therapeutic target discovery and clinical trials have been hindered by the heterogeneity of the disease, the lack of "druggable" driver mutations, and the dominance of large-scale genomic rearrangements. We have previously undertaken a comprehensive small-molecule phenotypic screen using the high-content Cell Painting assay to quantify the morphological response to a total of 19,555 small molecules across a panel of genetically distinct human esophageal cell lines to identify new therapeutic targets and small molecules for the treatment of esophageal adenocarcinoma. In this current study, we report for the first time the dose-response validation studies for the 72 screening hits from the target-annotated LOPAC and Prestwick FDA-approved compound libraries and the full list of 51 validated esophageal adenocarcinoma-selective small molecules (71% validation rate). We then focus on the most potent and selective hit molecules, elesclomol, disulfiram, and ammonium pyrrolidinedithiocarbamate. Using a multipronged, multitechnology approach, we uncover a unified mechanism of action and a vulnerability in esophageal adenocarcinoma toward copper-dependent cell death that could be targeted in the future.
Insights
Researchers identified 51 small molecules targeting esophageal adenocarcinoma by screening nearly 20,000 compounds. A key finding reveals a vulnerability to copper-dependent cell death, offering new therapeutic avenues for this challenging cancer.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Esophageal adenocarcinoma incidence is rising globally, with limited effective treatments and poor patient outcomes.
- Disease heterogeneity, lack of actionable mutations, and genomic complexity impede therapeutic target discovery.
Purpose of the Study:
- To identify novel therapeutic targets and small molecules for esophageal adenocarcinoma treatment.
- To validate hits from a large-scale phenotypic drug screen.
Main Methods:
- Conducted a high-content Cell Painting phenotypic screen of 19,555 small molecules across diverse esophageal cell lines.
- Performed dose-response validation for 72 screening hits from LOPAC and Prestwick libraries.
- Utilized a multipronged approach to investigate the mechanism of action for top-hit compounds.
Main Results:
- Validated 51 esophageal adenocarcinoma-selective small molecules, achieving a 71% validation rate.
- Identified elesclomol, disulfiram, and ammonium pyrrolidinedithiocarbamate as potent and selective hit molecules.
- Uncovered a unified mechanism of action involving copper-dependent cell death.
Conclusions:
- Esophageal adenocarcinoma exhibits a vulnerability to copper-dependent cell death.
- This copper-dependent pathway represents a promising future therapeutic target for esophageal adenocarcinoma.
