Cancer cell resistance to aurora kinase inhibitors: identification of novel targets for cancer therapy

J Proteome Res. 2013 Jan 4;12(1):455-69. doi: 10.1021/pr300819m. Epub 2012 Dec 10.

Abstract

Drug resistance is the major obstacle to successful cancer therapy. Our study focuses on resistance to Aurora kinase inhibitors tested as anti-cancer drugs in clinical trials. We have used 2D electrophoresis in the pH ranges of 4-7 and 6-11 followed by protein identification using MALDI-TOF/TOF to compare the protein composition of HCT116 colon cancer cells either sensitive to CYC116 and ZM447439 inhibitors or resistant toward these drugs. The analysis also included p53(+/+) and p53(-/-) phenotypes of HCT116 cells. Our findings demonstrate that platelet-activating factor acetylhydrolase and GTP-binding nuclear protein Ran contribute to the development of resistance to ZM447439 only where resistance is related to p53. On the other hand, serine hydroxymethyltransferase was found to promote the tumor growth in cells resistant to CYC116 without the influence of p53. Computer modeling of interaction networks highlighted a direct link of the p53-independent mechanism of resistance to CYC116 with autophagy. Importantly, serine hydroxymethyltransferase, serpin B5, and calretinin represent the target proteins that may help overcome resistance in combination therapies. In addition, serpin B5 and calretinin appear to be candidate biomarkers that may be accessible in patients for monitoring of cancer therapy with ease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Aurora Kinases
  • Benzamides / pharmacology*
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism
  • HCT116 Cells
  • Humans
  • Molecular Targeted Therapy
  • Neoplasms* / drug therapy
  • Neoplasms* / genetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyrimidines / pharmacology*
  • Quinazolines / pharmacology*
  • Thiazoles / pharmacology*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • 4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline
  • 4-methyl-5-(2-(4-morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine
  • Antineoplastic Agents
  • Benzamides
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Quinazolines
  • Thiazoles
  • Tumor Suppressor Protein p53
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • GTP-Binding Proteins