Ploidy Leads a Molecular Motor to Walk Different Paths to Drug Resistance
| Autor: | William M. Marsiglia, Alexander M. Real, Arvin C. Dar |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Clinical Biochemistry
Cell Drug Resistance Chemical biology Tumor cells macromolecular substances Computational biology Drug resistance Haploidy Biology Biochemistry Article chemistry.chemical_compound Neoplasms Drug Discovery Molecular motor medicine Humans Molecular Biology Pharmacology fungi Diploid cells Bridged Bicyclo Compounds Heterocyclic Diploidy medicine.anatomical_structure chemistry Molecular Medicine Growth inhibition Ploidy |
| Zdroj: | Cell Chem Biol |
| ISSN: | 2451-9456 |
| DOI: | 10.1016/j.chembiol.2020.06.019 |
| Popis: | 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 anti-cancer 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. |
| Databáze: | OpenAIRE |
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