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Half the Chromosome It Used to Be: Identifying Cancer Treatments Targeting Aneuploid Losses
Andrew O Disharoon1, Joe R Delaney1
1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Background/Objectives:
Aneuploidy is near-ubiquitous in cancer and can decrease chemotherapy efficacy while also sensitizing cells to other drugs.
Methods:
To systematically identify treatment strategies that target aneuploid cancers, data were integrated from The Cancer Genome Atlas (TCGA; 10,967 samples, 16,948 aneuploidy events) and the Broad Institute's Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) screen of 578 cancer cell lines and 4518 compounds.
Results:
Our analyses uncovered 37,720 significant positive and negative associations linking specific aneuploidies and treatments with patient prognosis or cell viability. Within TCGA data, 22 treatments correlated with improved 5-year survival for specific aneuploid cancers, whereas 46 were linked to worse outcomes. A complementary analysis of PRISM identified 17,946 compound-aneuploidy associations and 16,189 mechanism of action (MOA)-aneuploidy associations. Pathway-altering compounds that selectively reduce viability in cells with aneuploidy profiles were discovered, including an unexpectedly prominent number of glucocorticoid receptor agonists.
Conclusions:
This integrated dataset provides a resource for designing therapeutic decision hypotheses, identifying drug-repurposing opportunities, and informing future studies aimed at targeting aneuploidy-induced vulnerabilities in cancer.
Insights
This study identifies cancer treatments targeting aneuploidy, a common cancer trait. Findings link specific aneuploidies to survival outcomes and reveal compounds, like glucocorticoid receptor agonists, that selectively harm aneuploid cancer cells.
Area of Science:
- Genomics
- Cancer Biology
- Pharmacology
Background:
- Aneuploidy, a near-ubiquitous feature in cancer, impacts treatment efficacy.
- Aneuploid cancer cells exhibit altered sensitivity to various therapeutic agents.
Purpose of the Study:
- To systematically identify treatment strategies targeting cancers with aneuploidy.
- To uncover associations between specific aneuploidies, treatments, and patient outcomes or cell viability.
Main Methods:
- Integrated data from The Cancer Genome Atlas (TCGA) and the Broad Institute's PRISM screen.
- Analyzed 10,967 TCGA samples and 578 cancer cell lines treated with 4518 compounds.
- Examined 16,948 aneuploidy events and 16,189 mechanism of action (MOA)-aneuploidy associations.
Main Results:
- Discovered 37,720 significant associations between aneuploidies, treatments, and clinical outcomes.
- Identified 22 treatments improving 5-year survival in specific aneuploid cancers from TCGA data.
- Found 17,946 compound-aneuploidy associations and highlighted glucocorticoid receptor agonists as selectively toxic to aneuploid cells.
Conclusions:
- The integrated dataset serves as a resource for developing targeted cancer therapies.
- Identified potential drug-repurposing opportunities for treating aneuploid cancers.
- Informs future research on exploiting aneuploidy-induced vulnerabilities in cancer treatment.
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