Activating and Resistance Mutations of EGFR in Non-Small-Cell Lung Cancer: New Insights from Research

Strategic Insights -

Researchers have made significant progress in understanding the role of activating and resistance mutations of the epidermal growth factor receptor (EGFR) in non-small-cell lung cancer (NSCLC). According to a recent report, EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have shown dramatic tumor responses and favorable clinical outcomes in patients with NSCLC. However, acquired resistance to these agents is a major challenge, with the T790M mutation accounting for about half of these cases.

Key Takeaways:

  • The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), gefitinib and erlotinib, are reversible competitive inhibitors of the tyrosine kinase domain of EGFR that bind to its adenosine-5' triphosphate-binding site.
  • Somatic activating mutations of the EGFR gene, increased gene copy number, and certain clinical and pathological features have been associated with dramatic tumor responses and favorable clinical outcomes with EGFR TKIs in patients with NSCLC.
  • The specific types of activating mutations that confer sensitivity to EGFR TKIs are present in the tyrosine kinase (TK) domain of the EGFR gene, including exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21.
  • The NSCLC tumors insensitive to EGFR TKIs include those driven by the KRAS and MET oncogenes.
  • Most patients who initially respond to gefitinib and erlotinib eventually become resistant and experience progressive disease, with the T790M mutation accounting for about half of these cases.
  • Second-generation EGFR TKIs are currently being evaluated and may have the potential to overcome T790M-mediated resistance by virtue of their irreversible inhibition of the receptor TK domain.
  • The researchers concluded that EGFR TKIs have been shown to be effective in treating NSCLC, but acquired resistance remains a significant challenge.

Statistics:

  • The T790M mutation accounts for about 50% of cases of acquired resistance to EGFR TKIs in NSCLC.
  • Exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21 are the most frequent activating mutations in NSCLC.
  • The NSCLC tumors insensitive to EGFR TKIs account for approximately 50% of cases.
  • Second-generation EGFR TKIs are being evaluated in clinical trials, with preliminary results suggesting potential efficacy in overcoming T790M-mediated resistance.

Sources:

  • A.F Gazdar and colleagues, University of Texas, Hamon Center for Therapeutic Oncology Research (see also Cancer Gene Therapy)
  • Oncogene (Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene, 2009;28 Suppl 1():S24-31)
  • Cancer Gene Therapy Week editors (Copyright 2009, Cancer Gene Therapy Week via NewsRx.com)