Better survival with epidermal growth factor receptor exon 19 deletion than with exon 21 mutation in gefitinib-treated non-small cell lung cancer patients is due to differential inhibition of downstream signals

Abstract

14501 Background: Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Clinical data show different sensitivity to TKI treatment in patients with an EGFR exon 19 deletion versus L858R mutation. We investigated whether these two mutations produced differences in the phosphorylation of EGFR and downstream signal proteins, and in vitro sensitivity. Methods: This retrospective study analyzed NSCLC patients with an exon 19 deletion or exon 21 mutation of EGFR, comparing the response rate and overall survival with gefitinib treatment in these NSCLC patients. Two stable cell lines expressing these mutations were obtained by transfection of del746–750 and L858R mutation to an EGFR negative 293 cell line with a retrovirus system. Autophosphorylation of EGFR, Akt, and Erk was detected using Western blotting, and cell proliferation and inhibition tests were conducted to evaluate the bio-behavior of these cells. Results: Fifty-seven patients were included; 26 had a somatic mutation in exon 19 or 21. Patients with an exon 19 deletion had a median overall survival of 483 days, whereas median overall survival in those with the exon 21 point mutation was 168 days (p = 0.047) and the responsive rate were different among exon 19 deletion, exon 21 point mutation, wild type and double mutation. Based on Western blot analysis, gefitinib inhibited the autophosphorylation of EGFR, Akt, and Erk to a greater degree in exon 19 deletion cells than in L858R mutation cells. Gefitinib produced G1 arrest in more of the cells with an exon 19 deletion than with the L858R mutation and this arrestment was time relating. Conclusions: NSCLC patients with an EGFR exon 19 deletion survive longer following treatment with gefitinib than those with the exon 21 point mutation. This might be attributable to differences in inhibition of the autophosphorylation of EGFR and downstream signal proteins such as Akt and Erk. No significant financial relationships to disclose.