Inhibition of β-Catenin enhances the anticancer effect of irreversible EGFR-TKI in EGFR-mutated non-small-cell lung cancer with a T790M mutation.
BACKGROUND
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.


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.


CONCLUSIONS
Our findings indicate that β-Catenin might be a novel therapeutic target in EGFR-mutated NSCLC carrying the T790M mutation.
Departments of *Genome Biology and †Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka, Japan; and ‡Department of Medical Oncology, Kishiwada Municipal Hospital, Kishiwada, Japan.
Yosuke
Y
Togashi
Hidetoshi
H
Hayashi
Masato
M
Terashima
Marco A
MA
de Velasco
Kazuko
K
Sakai
Yoshihiko
Y
Fujita
Shuta
S
Tomida
Kazuhiko
K
Nakagawa
Kazuto
K
Nishio
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
C495270:CTNNB1 protein, human; D006575:Heterocyclic Compounds, 3-Ring; D047428:Protein Kinase Inhibitors; C544261:XAV939; D051176:beta Catenin; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin