Comparison of the cancer gene targeting and biochemical selectivities of all targeted kinase inhibitors approved for clinical use

PLoS One. 2014 Mar 20;9(3):e92146. doi: 10.1371/journal.pone.0092146. eCollection 2014.

Abstract

The anti-proliferative activities of all twenty-five targeted kinase inhibitor drugs that are in clinical use were measured in two large assay panels: (1) a panel of proliferation assays of forty-four human cancer cell lines from diverse tumour tissue origins; and (2) a panel of more than 300 kinase enzyme activity assays. This study provides a head-on comparison of all kinase inhibitor drugs in use (status Nov. 2013), and for six of these drugs, the first kinome profiling data in the public domain. Correlation of drug activities with cancer gene mutations revealed novel drug sensitivity markers, suggesting that cancers dependent on mutant CTNNB1 will respond to trametinib and other MEK inhibitors, and cancers dependent on SMAD4 to small molecule EGFR inhibitor drugs. Comparison of cellular targeting efficacies reveals the most targeted inhibitors for EGFR, ABL1 and BRAF(V600E)-driven cell growth, and demonstrates that the best targeted agents combine high biochemical potency with good selectivity. For ABL1 inhibitors, we computationally deduce optimized kinase profiles for use in a next generation of drugs. Our study shows the power of combining biochemical and cellular profiling data in the evaluation of kinase inhibitor drug action.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Gene Targeting*
  • Genetic Markers
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / genetics*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proteome / metabolism
  • Reproducibility of Results

Substances

  • Genetic Markers
  • Protein Kinase Inhibitors
  • Proteome

Grant support

This work was supported by a grant from the Innovation Office (Agentschap NL) of the Ministry of Economic Affairs of the Netherlands (INT 111039). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.