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Chromosome 20q amplification regulates in vitro response to Kinesin-5 inhibitor

Aimee L Jackson1, Mao Mao, Sumire Kobayashi

  • 1Rosetta Inpharmatics LLC, a wholly-owned subsidiary of Merck and Co., Inc., Seattle, WA 98109, USA. aimee_ jackson@merck.com

Cancer Informatics
|March 5, 2009
PubMed

Insights

Gene expression signatures predict response to Kinesin-5 inhibitors. Overexpression of AURKA, TPX2, and MYBL2, often amplified on chromosome 20q, confers resistance, suggesting therapeutic targeting strategies.

Area of Science:

  • Molecular oncology
  • Cancer genomics
  • Drug resistance mechanisms

Background:

  • Kinesin-5 inhibitors (Kinesin-5i) show promise as cancer therapeutics.
  • Identifying biomarkers for Kinesin-5i responsiveness is crucial for clinical application.
  • Chromosome 20q amplifications are common in various cancers and may influence drug response.

Purpose of the Study:

  • To identify gene expression signatures predicting sensitivity or resistance to Kinesin-5 inhibitors.
  • To investigate the role of chromosome 20q genes in mediating resistance to Kinesin-5i.
  • To explore potential therapeutic strategies for overcoming Kinesin-5i resistance.

Main Methods:

  • Analysis of gene expression signatures in cultured colon tumor cell lines.
  • siRNA-mediated knockdown of candidate genes located on chromosome 20q.
  • Assessment of gene disruption effects on Kinesin-5i sensitivity.

Main Results:

  • Gene expression signatures predicting Kinesin-5i responsiveness were identified.
  • Genes from chromosome 20q were enriched among those predicting resistance.
  • Disruption of AURKA, TPX2, and MYBL2 enhanced sensitivity to Kinesin-5i, indicating functional interaction and a role in resistance.

Conclusions:

  • Overexpression of AURKA, TPX2, and MYBL2, linked to 20q amplification, contributes to Kinesin-5i resistance.
  • Patients with tumors overexpressing AURKA due to 20q amplification may resist Kinesin-5 inhibitor treatment.
  • Inactivation of AURKA could sensitize resistant tumors to Kinesin-5 inhibitors, offering a potential therapeutic approach.
Keywords:
KIF11KSPRNAiaurora a kinasechromosome20q

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