Somatic mutations in epidermal growth factor receptor (
EGFR) found in lung adenocarcinomas are used as biomarkers
for the treatment with EGFR-tyrosine kinase inhibitors, including gefitinib. The bypass tracks with amplification of AXL is one
of the mechanisms underlying the resistance to gefitinib. We, therefore, carried out a candidate gene approach method to
identify
AXL polymorphisms associated with the effectiveness of gefitinib.
EGFR mutations were first identified by mutant-enriched PCR-restriction fragment length polymorphism (RFLP), and then 2 tag single nucleotide polymorphisms (SNPs) of
AXL were examined by PCR-RFLP in 62 Japanese patients with advanced lung adenocarcinoma and treated with gefitinib
in two general hospitals in Nagasaki. Subsequently, the association of
EFGR mutations and the
AXL polymorphism with the
effectiveness of gefitinib was examined in these patients. We next examined the effect of the
AXL polymorphism on the
expression and function of this gene. It is worthy of note that
EGFR mutations and the
AXL polymorphism rs6508974
independently contributed to the effectiveness of gefitinib, and the polymorphism was proved to be a possible biomarker for
selecting non-responders and responders to gefitinib treatment even in the absence of
EGFR mutations. Furthermore, this
SNP increased the transcriptional activity of the
AXL transcript variant 3, one of the three
AXL transcript variants, which to some
extent increased the epithelial-mesenchymal transition in cancer cells. Taken together,
AXL is one of the genes that determine
the effectiveness of gefitinib and a biomarker for selecting non-responders and responders among lung adenocarcinoma
patients with no
EGFR mutations, suggesting that rs6508974 in
AXL might be a functional SNP in lung adenocarcinoma.
View full abstract