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Development of a new mutation in EGFR leads to drug resistance in non-small cell lung cancer
  1. S Tate
  1. Specialist Registrar in Respiratory Medicine, Belfast City Hospital, Northern Ireland, UK;

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Epidermal growth factor receptor (EGFR) is frequently overexpressed and in an activated phosphorylated form in non-small-cell lung cancers (NSCLC). Response rates of 10–20% can be achieved with the use of anilinoquinazoline tyrosine kinase inhibitors targeted against EGFR although most patients eventually relapse. The majority of responsive tumours contain somatic mutations in the tyrosine kinase domain of the EGFR gene (small deletions or point mutations), which mediate the oncogenic effects but also confer the sensitivity to anilinoquinazoline inhibitors.

The authors report the case of a patient with EGFR mutant (delL747-S752), gefitinib responsive, advanced NSCLC who relapsed after 2 years of complete remission with gefitinib treatment. At relapse a transbronchial biopsy specimen of the tumour was found to contain a second point mutation (T790M) in the ATP binding cleft of the tyrosine kinase domain of EGFR. Molecular and structural studies elegantly showed that the second mutation sterically hindered access of gefitinib to its binding site in the tyrosine kinase domain, thereby inducing resistance to the drug. However, the oncogenic function of EGFR was unaffected by the second mutation.

Using test cells transfected with the mutated EGFR, the authors screened alternative EGFR inhibitors with different molecular structures and found at least one that inhibited the newly mutated receptor. Similar mechanisms of drug resistance have been demonstrated in chronic myeloid leukaemia and led to the development of second generation BCR-ABL inhibitors.

These results should encourage the development of alternative, molecularly targeted, EGFR inhibitors for patients with NSCLC who have acquired resistance to anilinoquinazoline inhibitors.

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