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Targeted therapies

No longer in the dark

Nature Reviews Cancer volume 4, pages 415–416 (2004)Cite this article

Results from early clinical trials with gefitinib — which is a small-molecule inhibitor of the epidermal growth factor receptor (EGFR) — caused great excitment among cancer researchers and clinicians alike. The data indicated that gefitinib would be active against non-small-cell lung cancer (NSCLC), a disease that often has overexpression of EGFR and for which chemotherapy is not very effective. However, large randomized trials only showed responses in a small subset of patients with NSCLC. Because of the rapid and dramatic response seen in this ∼10% of patients, gefitinib is now approved for third-line therapy of NSCLC.

Efficacy of gefitinib does not correlate with EGFR expression, so Lynch et al. hypothesized that mutations within the gene might be present that would distinguish responders from non-responders. Indeed, they found that heterozygous gain-of-function mutations were clustered within the tyrosine-kinase domain of EGFR — the active site where gefitinib binds — in tumour specimens analysed from eight of nine patients who had responded to gefitinib. Four of these patients had in-frame deletions within exon 19, and three of the patients had amino-acid substitutions within exon 21. Matched normal tissue from these patients did not contain the mutations and no mutations were seen in seven patients who had not responded to gefitinib. Paez et al. also examined samples from five patients treated with gefitinib for mutations in EGFR and found mutations similar to those in the study by Lynch et al.

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ORIGINAL RESEARCH PAPERS

  1. Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 29 April 2004 (doi:10.1056/NEJMoa040938)

  2. Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy Science 29 April 2004 (doi:10.1126/science.1099314)

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Authors
  1. Ezzie Hutchinson
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Hutchinson, E. No longer in the dark. Nat Rev Cancer 4, 415–416 (2004). https://doi.org/10.1038/nrc1376

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  • DOI: https://doi.org/10.1038/nrc1376

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