Dual epidermal growth factor receptor (EGFR)/insulin-like growth factor-1 receptor (IGF-1R) inhibitor: a novel approach for overcoming resistance in anticancer treatment

Eur J Pharmacol. 2011 Sep 30;667(1-3):56-65. doi: 10.1016/j.ejphar.2011.04.066. Epub 2011 May 30.

Abstract

Small molecule inhibitors of epidermal growth factor receptors (EGFR) have been found to show a good initial response in cancer patients but during the course of treatment, patients develop resistance after a few weeks of time. Development of secondary mutations or over-activation of insulin like growth factor (IGF-1R) pathway are a few of the several mechanisms proposed to explain the resistance. To study the effect of dual inhibition of EGFR and IGF-1R in overcoming the resistance, three strategies were envisaged and are reported in this manuscript: 1) a virtual predictive tumor model, 2) in vitro experimental data using a combination of EGFR and IGF-1R inhibitors and 3) in vitro experimental data using in house dual inhibitors. Findings reported in this manuscript suggest that simultaneous inhibition of IGF-1R and EGFR either by combination of two inhibitors or by dual kinase inhibitors is more efficacious compared to single agents. In vitro cell based experiments conducted using epidermoid cancer cell line, A431 and an EGFR mutant cell line, H1975 along with virtual predictions reported here suggests that dual inhibition of EGFR and IGF-1R is a viable approach to overcome EGFR resistance.

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Computational Biology
  • Cyclin D1 / metabolism
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Synergism
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mutation
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Quinazolines / pharmacology
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptor, IGF Type 1 / chemistry
  • Receptor, IGF Type 1 / metabolism

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Quinazolines
  • Cyclin D1
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Receptor, IGF Type 1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • pyrimidine