ArticleCell chemical biology2020
Distinct Mechanisms of Resistance to a CENP-E Inhibitor Emerge in Near-Haploid and Diploid Cancer Cells.
Article in Cell chemical biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed, 16 citations in OpenAlex.
- Molecular engineering of Cyanine-Hoechst hybrid materials for nanoscale DNA and chromatin imaging.JPhys materials · 2026Article
- Mitotic Machinery Dysregulation in Lung Cancer: Biological Roles, Therapeutic Targeting, and Combination Strategies.Pharmaceutics · 2026Review
- Kinesin-7 CENP-E mediates centrosome organization and spindle assembly to regulate chromosome alignment and genome stability.Cell proliferation · 2025Article
- Unveiling the Potential Role of Hesperetin and Emodin as a Combination Therapy to Inhibit the Pancreatic Cancer Progression against the C-Met Gene.Protein and peptide letters · 2025Article
- High expression levels of centromere protein O participates in cell proliferation of human ovarian cancer.Journal of ovarian research · 2024Article
- Kinesin-7 CENP-E in tumorigenesis: Chromosome instability, spindle assembly checkpoint, and applications.Frontiers in molecular biosciences · 2024Review
- CENPE Inhibition Leads to Mitotic Catastrophe and DNA Damage in Medulloblastoma Cells.Cancers · 2021Article
- Ploidy Leads a Molecular Motor to Walk Different Paths to Drug Resistance.Cell chemical biology · 2020Article
- A BODIPY-Hoechst conjugate for nuclear DNA staining.Journal of porphyrins and phthalocyaninesArticle
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3 authors at 2 institutions in 1 country.
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Abstract
Aberrant chromosome numbers in cancer cells may impose distinct constraints on the emergence of drug resistance-a major factor limiting the long-term efficacy of molecularly targeted therapeutics. However, for most anticancer drugs we lack analyses of drug-resistance mechanisms in cells with different karyotypes. Here, we focus on GSK923295, a mitotic kinesin CENP-E inhibitor that was evaluated in clinical trials as a cancer therapeutic. We performed unbiased selections to isolate inhibitor-resistant clones in diploid and near-haploid cancer cell lines. In diploid cells we identified single-point mutations that can suppress inhibitor binding. In contrast,transcriptome analyses revealed that the C-terminus of CENP-E was disrupted in GSK923295-resistant near-haploid cells. While chemical inhibition of CENP-E is toxic to near-haploid cells, knockout of the CENPE gene does not suppress haploid cell proliferation, suggesting that deletion of the CENP-E C-terminus can confer resistance to GSK923295. Together, these findings indicate that different chromosome copy numbers in cells can alter epistatic dependencies and lead to distinct modes of chemotype-specific resistance.
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