Phospho-kinase profile of colorectal tumors guides in the selection of multi-kinase inhibitors

Oncotarget. 2015 Oct 13;6(31):31272-83. doi: 10.18632/oncotarget.5211.


Protein kinases play a central role in the oncogenesis of colorectal tumors and are attractive druggable targets. Detection of activated kinases within a tumor could open avenues for drug selection and optimization of new kinase inhibitors. By using a phosphokinase arrays with human colorectal tumors we identified activated kinases, including the Epidermal Growth Factor Receptor (EGFR), components of the PI3K/mTOR pathway (AKT and S6), and STAT, among others. A pharmacological screening with kinase inhibitors against these proteins helped us to identify a new kinase inhibitor, termed EC-70124 that showed the highest anti-proliferative activity in cell lines. EC-70124 also inhibited cell migration and biochemical experiments demonstrated its effect targeting the PI3K/mTOR pathway. This drug also arrested cells at G2/M and induced apoptosis. Experiments in combination with standard chemotherapy used in the clinical setting indicated a synergistic effect. EC-70124 also reduced tumor growth in vivo and inhibited pS6 in the implanted tumors. In conclusion, by studying the kinase profile of colorectal tumors, we identified relevant activated pathways, and a new multi-kinase compound with significant antitumor properties.

Keywords: EC-70124; colon cancer; kinase inhibitors.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Aged
  • Aged, 80 and over
  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Neoplasm Staging
  • Prognosis
  • Protein Array Analysis
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / chemistry*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Protein Kinase Inhibitors
  • Protein Kinases