Cargando…
Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs
There is a high death rate of lung cancer patients. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in some lung adenocarcinoma patients with EGFR mutations. However, a significant number of patients show primary and acquire resistance to EGFR-TKIs. Although the...
Autores principales: | , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535059/ https://www.ncbi.nlm.nih.gov/pubmed/26268703 http://dx.doi.org/10.1038/srep13076 |
_version_ | 1782385552406872064 |
---|---|
author | Nakata, Asuka Yoshida, Ryo Yamaguchi, Rui Yamauchi, Mai Tamada, Yoshinori Fujita, Andre Shimamura, Teppei Imoto, Seiya Higuchi, Tomoyuki Nomura, Masaharu Kimura, Tatsuo Nokihara, Hiroshi Higashiyama, Masahiko Kondoh, Kazuya Nishihara, Hiroshi Tojo, Arinobu Yano, Seiji Miyano, Satoru Gotoh, Noriko |
author_facet | Nakata, Asuka Yoshida, Ryo Yamaguchi, Rui Yamauchi, Mai Tamada, Yoshinori Fujita, Andre Shimamura, Teppei Imoto, Seiya Higuchi, Tomoyuki Nomura, Masaharu Kimura, Tatsuo Nokihara, Hiroshi Higashiyama, Masahiko Kondoh, Kazuya Nishihara, Hiroshi Tojo, Arinobu Yano, Seiji Miyano, Satoru Gotoh, Noriko |
author_sort | Nakata, Asuka |
collection | PubMed |
description | There is a high death rate of lung cancer patients. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in some lung adenocarcinoma patients with EGFR mutations. However, a significant number of patients show primary and acquire resistance to EGFR-TKIs. Although the Akt kinase is commonly activated due to various resistance mechanisms, the key targets of Akt remain unclear. Here, we show that the Akt-β-catenin pathway may be a common resistance mechanism. We analyzed gene expression profiles of gefitinib-resistant PC9M2 cells that were derived from gefitinib-sensitive lung cancer PC9 cells and do not have known resistance mechanisms including EGFR mutation T790M. We found increased expression of Axin, a β-catenin target gene, increased phosphorylation of Akt and GSK3, accumulation of β-catenin in the cytoplasm/nucleus in PC9M2 cells. Both knockdown of β-catenin and treatment with a β-catenin inhibitor at least partially restored gefitinib sensitivity to PC9M2 cells. Lung adenocarcinoma tissues derived from gefitinib-resistant patients displayed a tendency to accumulate β-catenin in the cytoplasm. We provide a rationale for combination therapy that includes targeting of the Akt-β-catenin pathway to improve the efficacy of EGFR-TKIs. |
format | Online Article Text |
id | pubmed-4535059 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-45350592015-08-21 Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs Nakata, Asuka Yoshida, Ryo Yamaguchi, Rui Yamauchi, Mai Tamada, Yoshinori Fujita, Andre Shimamura, Teppei Imoto, Seiya Higuchi, Tomoyuki Nomura, Masaharu Kimura, Tatsuo Nokihara, Hiroshi Higashiyama, Masahiko Kondoh, Kazuya Nishihara, Hiroshi Tojo, Arinobu Yano, Seiji Miyano, Satoru Gotoh, Noriko Sci Rep Article There is a high death rate of lung cancer patients. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in some lung adenocarcinoma patients with EGFR mutations. However, a significant number of patients show primary and acquire resistance to EGFR-TKIs. Although the Akt kinase is commonly activated due to various resistance mechanisms, the key targets of Akt remain unclear. Here, we show that the Akt-β-catenin pathway may be a common resistance mechanism. We analyzed gene expression profiles of gefitinib-resistant PC9M2 cells that were derived from gefitinib-sensitive lung cancer PC9 cells and do not have known resistance mechanisms including EGFR mutation T790M. We found increased expression of Axin, a β-catenin target gene, increased phosphorylation of Akt and GSK3, accumulation of β-catenin in the cytoplasm/nucleus in PC9M2 cells. Both knockdown of β-catenin and treatment with a β-catenin inhibitor at least partially restored gefitinib sensitivity to PC9M2 cells. Lung adenocarcinoma tissues derived from gefitinib-resistant patients displayed a tendency to accumulate β-catenin in the cytoplasm. We provide a rationale for combination therapy that includes targeting of the Akt-β-catenin pathway to improve the efficacy of EGFR-TKIs. Nature Publishing Group 2015-08-13 /pmc/articles/PMC4535059/ /pubmed/26268703 http://dx.doi.org/10.1038/srep13076 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Nakata, Asuka Yoshida, Ryo Yamaguchi, Rui Yamauchi, Mai Tamada, Yoshinori Fujita, Andre Shimamura, Teppei Imoto, Seiya Higuchi, Tomoyuki Nomura, Masaharu Kimura, Tatsuo Nokihara, Hiroshi Higashiyama, Masahiko Kondoh, Kazuya Nishihara, Hiroshi Tojo, Arinobu Yano, Seiji Miyano, Satoru Gotoh, Noriko Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs |
title | Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs |
title_full | Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs |
title_fullStr | Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs |
title_full_unstemmed | Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs |
title_short | Elevated β-catenin pathway as a novel target for patients with resistance to EGF receptor targeting drugs |
title_sort | elevated β-catenin pathway as a novel target for patients with resistance to egf receptor targeting drugs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535059/ https://www.ncbi.nlm.nih.gov/pubmed/26268703 http://dx.doi.org/10.1038/srep13076 |
work_keys_str_mv | AT nakataasuka elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT yoshidaryo elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT yamaguchirui elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT yamauchimai elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT tamadayoshinori elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT fujitaandre elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT shimamurateppei elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT imotoseiya elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT higuchitomoyuki elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT nomuramasaharu elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT kimuratatsuo elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT nokiharahiroshi elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT higashiyamamasahiko elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT kondohkazuya elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT nishiharahiroshi elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT tojoarinobu elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT yanoseiji elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT miyanosatoru elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs AT gotohnoriko elevatedbcateninpathwayasanoveltargetforpatientswithresistancetoegfreceptortargetingdrugs |