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Molecular basis of drug resistance in aurora kinases

Fiona Girdler1, Fabio Sessa, Simona Patercoli

  • 1Faculty of Life Sciences, University of Manchester, Manchester, UK.

Chemistry & Biology
|June 19, 2008
PubMed

Insights

Drug resistance to Aurora kinase inhibitors may arise from mutations in Aurora B, impacting cancer therapy. These resistant Aurora B mutants could become new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Aurora kinases are crucial targets in cancer therapy, with several inhibitors in development.
  • The potential for clinical resistance to these Aurora kinase inhibitors is not well understood.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to Aurora kinase inhibitors.
  • To identify specific mutations in Aurora B that confer resistance to inhibitors.

Main Methods:

  • Utilized a hypermutagenic cancer cell line to select for resistance to the Aurora inhibitor ZM447439.
  • Characterized mutations in resistant clones, focusing on the ATP-binding pocket of Aurora B.

Main Results:

  • All resistant clones exhibited dominant point mutations in Aurora B.
  • Three identified mutations are located in the ATP-binding pocket, distinct from the gatekeeper residue.
  • Mutant Aurora B retained wild-type catalytic activity and showed resistance to multiple Aurora inhibitors.

Conclusions:

  • Drug-resistant Aurora B mutants are predicted to emerge during clinical treatment.
  • The adaptability of the Aurora B ATP-binding pocket confers resistance to multiple inhibitors.
  • Drug-resistant Aurora B mutants represent potential novel therapeutic targets.

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