INTRODUCTION: Patients with non-small-cell lung cancer (NSCLC) with somatic 
activating mutations of the epidermal growth factor receptor gene (EGFR 
mutations) generally respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). 
β-Catenin is a key component of the Wnt/β-Catenin signal and is an important 
oncogene that is involved in the pathogenesis and progression of malignant 
tumors, especially cancer stem cells.
METHODS AND RESULTS: We found that EGFR-mutated NSCLC cell lines exhibited a 
high expression level of β-Catenin, compared with cell lines with the wild-type 
EGFR gene, and XAV939 (a β-Catenin inhibitor) enhanced the sensitivities to 
EGFR-TKI in EGFR-mutated NSCLC cell lines. In EGFR-mutated NSCLC cell lines with 
the acquired resistance threonine-to-methionine mutation in codon 790 (T790M) 
mutation, XAV939 enhanced the sensitivity of the cells to an irreversible 
EGFR-TKI but not a reversible EGFR-TKI. The combination of XAV939 and EGFR-TKIs 
strongly inhibited the β-Catenin signal and strongly decreased the 
phosphorylation of EGFR, compared with the use of EGFR-TKIs alone, suggesting an 
interaction between EGFR and the β-Catenin signal. The stem cell-like properties 
of the EGFR-mutated cell line carrying the T790M mutation were inhibited by 
XAV939 and BIBW2992 (an irreversible EGFR-TKI). Furthermore, the stem cell-like 
properties were strongly inhibited by a combination of both the agents. A 
xenograft study demonstrated that β-Catenin knockdown enhanced the antitumor 
effect of BIBW2992 in the EGFR-mutated NSCLC cell line carrying the T790M 
mutation.
CONCLUSION: Our findings indicate that β-Catenin might be a novel therapeutic 
target in EGFR-mutated NSCLC carrying the T790M mutation.