The aberrant activation of the epidermal-growth-factor receptor (EGFR) is a contributing factor to the development of lung cancer. James Alvarez and colleagues now show that the EGFR-mediated activation of one member of a family of transcription factors seems to be crucial for this process.

The activation of EGFR induces a cascade of signal-transduction pathways that includes the signal transducer and activator of transcription (STAT) family. There is good evidence that STAT3 (and STAT5) is activated in response to EGFR activity, so the authors investigated whether STAT3 activity is necessary for the oncogenic effects of mutant EGFR.

STAT3 is activated as a result of phosphorylation on tyrosine 705 and serine 727. The authors showed that this phosphorylation is dependent on EGFR kinase activity in NIH3T3 fibroblasts expressing EGFR mutants that are found in non-small-cell lung cancer (NSCLC). However, when verifying these findings in two human NSCLC cell lines with EGFR mutations, only phosphorylation of serine 727 proved to be dependent on the kinase activity of mutant EGFR. Nevertheless, the use of short interfering RNAs to inhibit STAT3, or dominant-negative STAT3 mutants, showed that STAT3 activity enhanced the survival of these NSCLC cell lines. Moreover, inhibition of STAT3 increased the sensitivity of these cells to the EGFR inhibitor gefitinib.

If STAT3 does mediate the oncogenic effects of mutant EGFR, then one would expect STAT3 target genes to be expressed in lung tumours that have mutant EGFR. To analyse this, the authors sequenced EGFR in 127 lung adenocarcinomas for which microarray gene-expression data were already available. By comparing the tumours with the EGFR kinase mutations with those without, the authors were able to show, using a previously identified activated STAT3 gene-signature set from breast cancer samples, that lung adenocarcinomas with mutant EGFR showed enrichment for the activated STAT3 gene-signature profile.

The authors conclude that studying mutant EGFR-mediated signal transduction, including activation of STAT3, should help to further our understanding of the response of lung tumours to EGFR inhibitors. Their findings also indicate that the use of STAT3-based inhibitors might have a beneficial effect.