Inhibition of CPAP-tubulin interaction prevents proliferation of centrosome-amplified cancer cells

EMBO J. 2019 Jan 15;38(2):e99876. doi: 10.15252/embj.201899876. Epub 2018 Dec 10.


Centrosome amplification is a hallmark of human cancers that can trigger cancer cell invasion. To survive, cancer cells cluster amplified extra centrosomes and achieve pseudobipolar division. Here, we set out to prevent clustering of extra centrosomes. Tubulin, by interacting with the centrosomal protein CPAP, negatively regulates CPAP-dependent peri-centriolar material recruitment, and concurrently microtubule nucleation. Screening for compounds that perturb CPAP-tubulin interaction led to the identification of CCB02, which selectively binds at the CPAP binding site of tubulin. Genetic and chemical perturbation of CPAP-tubulin interaction activates extra centrosomes to nucleate enhanced numbers of microtubules prior to mitosis. This causes cells to undergo centrosome de-clustering, prolonged multipolar mitosis, and cell death. 3D-organotypic invasion assays reveal that CCB02 has broad anti-invasive activity in various cancer models, including tyrosine kinase inhibitor (TKI)-resistant EGFR-mutant non-small-cell lung cancers. Thus, we have identified a vulnerability of cancer cells to activation of extra centrosomes, which may serve as a global approach to target various tumors, including drug-resistant cancers exhibiting high incidence of centrosome amplification.

Keywords: CCB02; CPAP‐tubulin module; centrosome activation; centrosome clustering; centrosomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Centrosome / drug effects
  • Centrosome / metabolism*
  • Drug Screening Assays, Antitumor
  • Female
  • HeLa Cells
  • Humans
  • Mice
  • Microtubule-Associated Proteins / metabolism*
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Protein Binding / drug effects
  • Small Molecule Libraries / administration & dosage*
  • Small Molecule Libraries / pharmacology
  • Tubulin / metabolism*
  • Xenograft Model Antitumor Assays


  • CENPJ protein, human
  • Microtubule-Associated Proteins
  • Small Molecule Libraries
  • Tubulin