Inhibition of β-Catenin Enhances the Anticancer Effect of Irreversible EGFR-TKI in EGFR-Mutated Non–small-cell Lung Cancer with a T790M Mutation. Issue 1 (January 2015)

• Record Type: Journal Article
• Authors: Togashi, Yosuke; Hayashi, Hidetoshi; Terashima, Masato; de Velasco, Marco A; Sakai, Kazuko; Fujita, Yoshihiko; Tomida, Shuta; Nakagawa, Kazuhiko; Nishio, Kazuto
• Is Part Of: Journal of thoracic oncology. Volume 10:Issue 1(2015)
• Publication Date: 2015-01
• Subjects: Non-small-cell lung cancer -- Epidermal growth factor receptor T790M mutation -- Epidermal growth factor receptor tyrosine kinase inhibitor -- β-Catenin -- Stem cell-like properties; Chest -- Cancer -- Periodicals; Thoracic Neoplasms -- Periodicals; 616.99494005
• DOI: 10.1097/JTO.0000000000000353
• Languages: English
• ISSNs: 1556-0864

Abstract

Abstract : 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.