Abstract 5440: Role of tyrosine phosphorylation of β-catenin in EGFR-mutant lung cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.5440-5440
• Main Authors: Fujii, Masanori, Nakayama, Sohei, Shimizu, Kohei, Takei, Hisashi, Ando, Mariko, Heo, Eunyoung, Kobayashi, ikei, Pan, Gilbert, Inuzuka, Hiroyuki, Kobayashi, Susumu
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-5440

Wnt/ β-catenin signaling plays a key role in the pathogenesis of colon and other cancers. Emerging evidence indicates that oncogenic β-catenin regulates several biological processes essential for cancer initiation and progression. The role of β-catenin in lung cancer with epidermal growth factor receptor (EGFR) activating mutations has not been fully understood; however, recent studies suggest that co-occurring genetic alterations in CTNNB1 might cooperate with mutant EGFR in promoting tumor progression and treatment resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). This sheds new light on this pathway in EGFR-mutant lung cancer. We previously demonstrated that β-catenin plays an essential role in lung tumorigenesis driven by EGFR mutants, particularly EGFR-T790M. We also found that β-catenin is activated through tyrosine-phosphorylation by EGFR mutants. In this study, we identified five tyrosine phosphorylation sites (Y5) of β-catenin by mass spectrometry. Tyrosine phosphorylation at these sites may be critical in β-catenin stability, nuclear translocation and its role as a transcriptional switch in oncogenesis. Firstly, we demonstrated that tyrosine phosphorylation of β-catenin disrupts the binding of a main ubiquitin ligase β-Trcp1, leading to an escape from degradation. Secondly, in contrast to known transcriptional activity with TCF/LEF, β-catenin that is tyrosine phosphorylated by mutant EGFR was found to form a complex with a transcriptional regulator, YAP1, and a transcriptional factor, TBX5. Immunoprecipitation experiments suggested Y5 tyrosine phosphorylation of β-catenin plays a critical role in the interaction between β-catenin and TBX5. Moreover, this complex may regulate anti-apoptotic genes, including BCL2L1, which encodes Bcl-xL. Combination treatment with osimertinib, a 3rd generation EGFR-TKI, and dasatinib suppressed Y5 tyrosine phosphorylation of β-catenin, leading to reduced Bcl-xL expression. Subsequent TBX5 knockdown in vitro decreased Bcl-xL expression while Bcl2l1 knockout in vivo mouse models suppressed lung tumor development. These observations suggest that β-catenin-YAP1-TBX5 complex contributes to EGFR-T790M lung cancer and may serve to explain the underlying mechanism for EGFR-TKIs resistance and for the effectiveness of combination therapy with osimertinib and dasatinib. Citation Format: Masanori Fujii, Sohei Nakayama, Kohei Shimizu, Hisashi Takei, Mariko Ando, Eunyoung Heo, ikei Kobayashi, Gilbert Pan, Hiroyuki Inuz