β-catenin contributes to lung tumor development induced by EGFR mutations

Sohei Nakayama, Natasha Sng, Julian Carretero, Robert Welner, Yuichiro Hayashi, Mihoko Yamamoto, Alistair J. Tan, Norihiro Yamaguchi, Hiroyuki Yasuda, Danan Li, Kenzo Soejima, Ross A. Soo, Daniel B. Costa, Kwok Kin Wong, Susumu S. Kobayashi

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 b-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.

Original languageEnglish
Pages (from-to)5891-5902
Number of pages12
JournalCancer Research
Volume74
Issue number20
DOIs
Publication statusPublished - 2014 Oct 15

Fingerprint

Catenins
Lung
Mutation
Neoplasms
Lung Neoplasms
Gene Deletion
Protein-Tyrosine Kinases
Transgenic Mice
Transcriptional Activation
Tyrosine
Carcinogenesis
Therapeutics
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Nakayama, S., Sng, N., Carretero, J., Welner, R., Hayashi, Y., Yamamoto, M., ... Kobayashi, S. S. (2014). β-catenin contributes to lung tumor development induced by EGFR mutations. Cancer Research, 74(20), 5891-5902. https://doi.org/10.1158/0008-5472.CAN-14-0184

β-catenin contributes to lung tumor development induced by EGFR mutations. / Nakayama, Sohei; Sng, Natasha; Carretero, Julian; Welner, Robert; Hayashi, Yuichiro; Yamamoto, Mihoko; Tan, Alistair J.; Yamaguchi, Norihiro; Yasuda, Hiroyuki; Li, Danan; Soejima, Kenzo; Soo, Ross A.; Costa, Daniel B.; Wong, Kwok Kin; Kobayashi, Susumu S.

In: Cancer Research, Vol. 74, No. 20, 15.10.2014, p. 5891-5902.

Research output: Contribution to journalArticle

Nakayama, S, Sng, N, Carretero, J, Welner, R, Hayashi, Y, Yamamoto, M, Tan, AJ, Yamaguchi, N, Yasuda, H, Li, D, Soejima, K, Soo, RA, Costa, DB, Wong, KK & Kobayashi, SS 2014, 'β-catenin contributes to lung tumor development induced by EGFR mutations', Cancer Research, vol. 74, no. 20, pp. 5891-5902. https://doi.org/10.1158/0008-5472.CAN-14-0184
Nakayama, Sohei ; Sng, Natasha ; Carretero, Julian ; Welner, Robert ; Hayashi, Yuichiro ; Yamamoto, Mihoko ; Tan, Alistair J. ; Yamaguchi, Norihiro ; Yasuda, Hiroyuki ; Li, Danan ; Soejima, Kenzo ; Soo, Ross A. ; Costa, Daniel B. ; Wong, Kwok Kin ; Kobayashi, Susumu S. / β-catenin contributes to lung tumor development induced by EGFR mutations. In: Cancer Research. 2014 ; Vol. 74, No. 20. pp. 5891-5902.
@article{a42c299b35284aeaad025588d06a367c,
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 b-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.",
author = "Sohei Nakayama and Natasha Sng and Julian Carretero and Robert Welner and Yuichiro Hayashi and Mihoko Yamamoto and Tan, {Alistair J.} and Norihiro Yamaguchi and Hiroyuki Yasuda and Danan Li and Kenzo Soejima and Soo, {Ross A.} and Costa, {Daniel B.} and Wong, {Kwok Kin} and Kobayashi, {Susumu S.}",
year = "2014",
month = "10",
day = "15",
doi = "10.1158/0008-5472.CAN-14-0184",
language = "English",
volume = "74",
pages = "5891--5902",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "20",

}

TY - JOUR

T1 - β-catenin contributes to lung tumor development induced by EGFR mutations

AU - Nakayama, Sohei

AU - Sng, Natasha

AU - Carretero, Julian

AU - Welner, Robert

AU - Hayashi, Yuichiro

AU - Yamamoto, Mihoko

AU - Tan, Alistair J.

AU - Yamaguchi, Norihiro

AU - Yasuda, Hiroyuki

AU - Li, Danan

AU - Soejima, Kenzo

AU - Soo, Ross A.

AU - Costa, Daniel B.

AU - Wong, Kwok Kin

AU - Kobayashi, Susumu S.

PY - 2014/10/15

Y1 - 2014/10/15

N2 - 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 b-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.

AB - 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 b-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.

UR - http://www.scopus.com/inward/record.url?scp=84908131492&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908131492&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-14-0184

DO - 10.1158/0008-5472.CAN-14-0184

M3 - Article

C2 - 25164010

AN - SCOPUS:84908131492

VL - 74

SP - 5891

EP - 5902

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 20

ER -