Aurora B expression modulates paclitaxel response in non-small cell lung cancer

Ahmed Sk Al-Khafaji, Michael Pa Davies, Janet M Risk, Michael W Marcus, Maria Koffa, John R Gosney, Richard J Shaw, John K Field, Triantafillos Liloglou*

*Corresponding author for this work

Research output: Contribution to journalArticle (journal)peer-review

40 Citations (Scopus)

Abstract

BACKGROUND: Taxanes are mitotic poisons widely used in the treatment of non-small cell lung cancer (NSCLC), however, little is known about potential molecular modulators of response to these compounds. Aurora B (AURKB) is a critical regulator of the mitotic spindle assembly, previously shown overexpressed in NSCLC. Here we investigated the hypothesis that AURKB expression modulates the efficacy of taxanes in NSCLC cells.

METHODS: AURKB mRNA expression was determined by qPCR in 132 frozen NSCLC tissues and nine NSCLC cell lines. Aurora B expression was knocked down in cell lines using multiple shRNA constructs. Barasertib was used to specifically inhibit AURKB activity, determined by the level of H3S10 phosphorylation.

RESULTS: Frequent AURKB mRNA upregulation was observed in NSCLC tissues (P<0.0001), being more prominent in squamous carcinomas (P<0.0001). Aurora B expression in cell lines strongly correlated with sensitivity to both docetaxel (P=0.004) and paclitaxel (P=0.007). Aurora B knockdown derivatives consistently showed a dose-dependent association between low-AURKB expression and resistance to paclitaxel. Specific chemical inhibition of Aurora B activity also demonstrated a strong dose-dependent efficiency in triggering paclitaxel resistance.

CONCLUSIONS: Aurora B activity is an important modulator of taxane response in NSCLC cells. This may lead to further insights into taxane sensitivity of NSCLC tumours.

Original languageEnglish
Pages (from-to)592-599
Number of pages8
JournalBritish Journal of Cancer
Volume116
Issue number5
DOIs
Publication statusPublished - 28 Feb 2017

Keywords

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents, Phytogenic/therapeutic use
  • Aurora Kinase B/genetics
  • Carcinoma, Non-Small-Cell Lung/drug therapy
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic/drug effects
  • Humans
  • Lung Neoplasms/drug therapy
  • Male
  • Middle Aged
  • Organophosphates/pharmacology
  • Paclitaxel/therapeutic use
  • Quinazolines/pharmacology
  • Up-Regulation/drug effects

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