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Gefitinib (Iressa) targets the tyrosine kinase epidermal growth factor receptor (EGFR) but the presence of EGFR on tumour cells does not predict response to treatment and in clinical trials only a few patients with non-small cell lung cancer (NSCLC) show any response. In this study the authors sequenced the EGFR gene in NSCLC tumours and found somatic mutations in the tyrosine kinase domain in eight of nine patients who had responded to treatment with gefitinib. Mutations were not found in matched normal tissue from these patients, or in seven patients who had no response to gefitinib (p<0.001). When the most common mutation was transfected into cell lines, enhanced tyrosine kinase signalling was seen in response to EGF compared with the wild type gene and there was an increased sensitivity to in vitro inhibition by gefitinib.
This paper, together with a similar study published recently in Science, raises hope that patients whose tumours will respond to gefitinib could be prospectively identified. On a wider level, it reveals a higher level of complexity in the concept of “targeted therapy”: even when key molecular tumour targets have been identified, further work may be required to determine which subgroups will respond.