1. ¹Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan, ROC
2. ²Institute of Genetics and Genome Research Center, National Yang-Ming University, Taipei, Taiwan, ROC
3. ³Department of Pathology, Chang Gung Memorial Hospital, Taipei, Taiwan, ROC

Correspondence: Dr Y-R Chen, Division of Molecular and Genomic Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC. E-mail: yrchen@nhri.org.tw

Received 23 February 2007; Revised 22 May 2007; Accepted 10 June 2007; Published online 23 July 2007.

Abstract

Mutations in epidermal growth factor receptor (EGFR) kinase domain associate with clinical responses to EGFR inhibitors and are frequently observed in non-small cell lung cancer (NSCLC) patients in East Asian populations. Clinically identified EGFR mutations cause constitutive receptor activation. The activating mechanisms were unclear but appeared to be different among EGFR mutants. We found that EGFR mutants had different sensitivity to an Src inhibitor PP2. S768I and L861Q mutants were less sensitive to Src suppression than others. Mutation at tyrosine 869 (845) residue, an Src phosphorylation site, decreased the phosphorylation levels of wild-type EGFR and other mutants, but not that of S768I and L861Q mutants, suggesting that S768I and L861Q mutants became Src independent for their activation and biological functions. In contrast, cells expressing EGFR-L858R or exon 19 deletion mutants were more sensitive to PP2 than cells expressing wild-type EGFR. Interestingly, EGFR with exon 19-deletion/T790M double mutations, which was resistant to gefitinib, remained sensitive to PP2. Taken together, our data indicate that Src inhibitors might be effective in treating NSCLC harboring specific types of EGFR mutations.