Spindle assembly checkpoint gene expression in childhood adrenocortical tumors (ACT): Overexpression of Aurora kinases A and B is associated with a poor prognosis

Pediatr Blood Cancer. 2013 Nov;60(11):1809-16. doi: 10.1002/pbc.24653. Epub 2013 Jun 20.

Abstract

Background: Pediatric adrenocortical tumors (ACT) are rare malignancies and treatment has a small impact on survival in advanced disease and the discovery of potential target genes could be important in new therapeutic approaches.

Methods: The mRNA expression levels of spindle checkpoint genes AURKA, AURKB, BUB, and BUBR1 were analyzed in 60 children with ACT by quantitative real time PCR. The anticancer effect of ZM447439, an experimental AURK inhibitor, was analyzed in a primary childhood ACT culture carrying the TP53 p.R337H mutation.

Results: A significant association was observed between malignancy as defined by Weiss score ≥3 and higher AURKA (2.0-fold, P = 0.01), AURKB (7.0-fold, P = 0.007), and BUBR1 (5.8-fold, P = 0.007) gene expression, and between unfavorable event (death or relapse) and higher expression of AURKA (6.0-fold, P = 0.034) and AURKB (17-fold, P = 0.013). Overexpression of AURKA and AURKB was associated with lower event-free survival in uni- (P < 0.001 and P = 0.006, respectively) and multivariate (P = 0.002 and P = 0.03, respectively) analysis. Significant lower Event free survival (EFS) was also observed in patients with moderate/strong immunostaining to AURKA (P = 0.012) and AURKB (P = 0.045). ZM447439 was able to induce inhibition of proliferation and colony formation in a primary childhood ACT culture carrying the TP53 p.R337H mutation.

Conclusion: Our results suggest that AURKA and AURKB overexpression in pediatric ACT may be related to more aggressive disease and the inhibition of these proteins could be an interesting approach for the treatment of these tumors.

Keywords: AURK; adrenocortical tumor; childhood; prognosis; spindle assembly checkpoint genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenocortical Carcinoma / enzymology*
  • Adrenocortical Carcinoma / genetics*
  • Adrenocortical Carcinoma / pathology
  • Antineoplastic Agents / pharmacology
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinases
  • Benzamides / pharmacology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Disease-Free Survival
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Immunohistochemistry
  • Infant
  • Kaplan-Meier Estimate
  • M Phase Cell Cycle Checkpoints / genetics*
  • Male
  • Prognosis
  • Proportional Hazards Models
  • Protein-Serine-Threonine Kinases / biosynthesis*
  • Protein-Serine-Threonine Kinases / genetics
  • Quinazolines / pharmacology
  • RNA, Messenger / analysis
  • Real-Time Polymerase Chain Reaction
  • Transcriptome

Substances

  • 4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline
  • Antineoplastic Agents
  • Benzamides
  • Enzyme Inhibitors
  • Quinazolines
  • RNA, Messenger
  • AURKA protein, human
  • AURKB protein, human
  • Aurora Kinase A
  • Aurora Kinase B
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases

Supplementary concepts

  • Adrenocortical Carcinoma, Pediatric