Three generations of epidermal growth factor receptor tyrosine kinase inhibitors developed to revolutionize the therapy of lung cancer

Drug Des Devel Ther. 2016 Nov 24;10:3867-3872. doi: 10.2147/DDDT.S119162. eCollection 2016.

Abstract

Lung cancer, ~80%-85% of which is non-small-cell lung cancer (NSCLC), is the leading cause of cancer-related mortality worldwide. Sensitizing mutations in epidermal growth factor receptor (EGFR) gene (EGFRm+), such as exon 19 deletions and exon 21 L858R point mutations, are the most important drivers in NSCLC patients. In this respect, small-molecule EGFR tyrosine kinase inhibitors (TKIs) have been designed and developed, which launched the era of targeted, personalized and precise medicine for lung cancer. Patients with EGFRm+ could achieve good responses to the treatment with the first-generation EGFR TKIs, such as erlotinib and gefitinib. However, most patients develop acquired drug resistance mostly driven by the T790M mutation occurring within exon 20. Although the second-generation EGFR TKIs, such as afatinib, dacomitinib and neratinib, demonstrated promising activity against T790M in preclinical models, they have failed to overcome resistance in patients due to dose-limiting toxicity. Recently, the third-generation EGFR TKIs have shown to be effective against cell lines and murine models harboring T790M mutations while sparing wild-type EGFR, which represents a promising breakthrough approach in overcoming T790M-mediated resistance in NSCLC patients. This article provides a comprehensive review of the therapy revolution for NSCLC with three generations of EGFR TKIs.

Keywords: T790M mutation; epidermal growth factor receptor; lung cancer; tyrosine kinase inhibitors.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Drug Design
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Molecular Targeted Therapy
  • Mutation
  • Protein Kinase Inhibitors / therapeutic use*

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • EGFR protein, human
  • ErbB Receptors