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  2. Distinct Mechanisms of Resistance to a CENP-E Inhibitor Emerge in Near-Haploid and Diploid Cancer Cells

Distinct Mechanisms of Resistance to a CENP-E Inhibitor Emerge in Near-Haploid and Diploid Cancer Cells

  • Cell Chem Biol. 2020 Jul 16;27(7):850-857.e6. doi: 10.1016/j.chembiol.2020.05.003.
Rudolf Pisa 1 Donovan Y Z Phua 2 Tarun M Kapoor 3
Affiliations

Affiliations

  • 1 Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, USA; Tri-Institutional PhD Program in Chemical Biology, The Rockefeller University, New York, NY 10065, USA.
  • 2 Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, USA; Laboratory of Structural Biophysics and Mechanobiology, The Rockefeller University, New York, NY 10065, USA.
  • 3 Laboratory of Chemistry and Cell Biology, The Rockefeller University, New York, NY 10065, USA. Electronic address: kapoor@rockefeller.edu.
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.

Keywords

CENP-E; GSK923295; HCT116; KBM7; chemical inhibitor; chromosome copy number; kinesin; ploidy; resistance; target ID.

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