title: β-catenin contributes to lung tumor development induced by EGFR mutations.
abstract: The discovery of somatic mutations in EGFR and development of EGFR tyrosine kinase inhibitors (TKI) have revolutionized treatment for lung cancer. However, resistance to TKIs emerges in almost all patients and currently no effective treatment is available. Here, we show that β-catenin is essential for development of EGFR-mutated lung cancers. β-Catenin was upregulated and activated in EGFR-mutated cells. Mutant EGFR preferentially bound to and tyrosine phosphorylated β-catenin, leading to an increase in β-catenin-mediated transactivation, particularly in cells harboring the gefitinib/erlotinib-resistant gatekeeper EGFR-T790M mutation. Pharmacologic inhibition of β-catenin suppressed EGFR-L858R-T790M mutated lung tumor growth, and genetic deletion of the β-catenin gene dramatically reduced lung tumor formation in EGFR-L858R-T790M transgenic mice. These data suggest that β-catenin plays an essential role in lung tumorigenesis and that targeting the β-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs.
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sohei
authors.initials: S
authors.lastname: Nakayama
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Natasha
authors.initials: N
authors.lastname: Sng
authors.affiliation: Department of Physiology, University of Valencia, Burjassot, Spain.
authors.forename: Julian
authors.initials: J
authors.lastname: Carretero
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Robert
authors.initials: R
authors.lastname: Welner
authors.affiliation: Department of Pathology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Tan
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Yamaguchi
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Department of Pulmonary Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Danan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pulmonary Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Soejima
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore. Department of Haematology-Oncology, National University Health System, Singapore.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Soo
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Harvard Stem Cell Institute, Cambridge, Massachusetts. skobayas@bidmc.harvard.edu.
authors.forename: Susumu S
authors.initials: SS
authors.lastname: Kobayashi
mesh_terms: D000077716:Afatinib; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D063646:Carcinogenesis / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004318:Doxycycline / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008822:Mice, Transgenic; D020125:Mutation, Missense; D055550:Protein Stability; D011799:Quinazolines / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D011799:Quinazolines; D051176:beta Catenin; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D004318:Doxycycline