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AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells

A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback...

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Autores principales: Taniguchi, Hirokazu, Yamada, Tadaaki, Wang, Rong, Tanimura, Keiko, Adachi, Yuta, Nishiyama, Akihiro, Tanimoto, Azusa, Takeuchi, Shinji, Araujo, Luiz H., Boroni, Mariana, Yoshimura, Akihiro, Shiotsu, Shinsuke, Matsumoto, Isao, Watanabe, Satoshi, Kikuchi, Toshiaki, Miura, Satoru, Tanaka, Hiroshi, Kitazaki, Takeshi, Yamaguchi, Hiroyuki, Mukae, Hiroshi, Uchino, Junji, Uehara, Hisanori, Takayama, Koichi, Yano, Seiji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335418/
https://www.ncbi.nlm.nih.gov/pubmed/30651547
http://dx.doi.org/10.1038/s41467-018-08074-0
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author Taniguchi, Hirokazu
Yamada, Tadaaki
Wang, Rong
Tanimura, Keiko
Adachi, Yuta
Nishiyama, Akihiro
Tanimoto, Azusa
Takeuchi, Shinji
Araujo, Luiz H.
Boroni, Mariana
Yoshimura, Akihiro
Shiotsu, Shinsuke
Matsumoto, Isao
Watanabe, Satoshi
Kikuchi, Toshiaki
Miura, Satoru
Tanaka, Hiroshi
Kitazaki, Takeshi
Yamaguchi, Hiroyuki
Mukae, Hiroshi
Uchino, Junji
Uehara, Hisanori
Takayama, Koichi
Yano, Seiji
author_facet Taniguchi, Hirokazu
Yamada, Tadaaki
Wang, Rong
Tanimura, Keiko
Adachi, Yuta
Nishiyama, Akihiro
Tanimoto, Azusa
Takeuchi, Shinji
Araujo, Luiz H.
Boroni, Mariana
Yoshimura, Akihiro
Shiotsu, Shinsuke
Matsumoto, Isao
Watanabe, Satoshi
Kikuchi, Toshiaki
Miura, Satoru
Tanaka, Hiroshi
Kitazaki, Takeshi
Yamaguchi, Hiroyuki
Mukae, Hiroshi
Uchino, Junji
Uehara, Hisanori
Takayama, Koichi
Yano, Seiji
author_sort Taniguchi, Hirokazu
collection PubMed
description A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.
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spelling pubmed-63354182019-01-18 AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells Taniguchi, Hirokazu Yamada, Tadaaki Wang, Rong Tanimura, Keiko Adachi, Yuta Nishiyama, Akihiro Tanimoto, Azusa Takeuchi, Shinji Araujo, Luiz H. Boroni, Mariana Yoshimura, Akihiro Shiotsu, Shinsuke Matsumoto, Isao Watanabe, Satoshi Kikuchi, Toshiaki Miura, Satoru Tanaka, Hiroshi Kitazaki, Takeshi Yamaguchi, Hiroyuki Mukae, Hiroshi Uchino, Junji Uehara, Hisanori Takayama, Koichi Yano, Seiji Nat Commun Article A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells. Nature Publishing Group UK 2019-01-16 /pmc/articles/PMC6335418/ /pubmed/30651547 http://dx.doi.org/10.1038/s41467-018-08074-0 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Taniguchi, Hirokazu
Yamada, Tadaaki
Wang, Rong
Tanimura, Keiko
Adachi, Yuta
Nishiyama, Akihiro
Tanimoto, Azusa
Takeuchi, Shinji
Araujo, Luiz H.
Boroni, Mariana
Yoshimura, Akihiro
Shiotsu, Shinsuke
Matsumoto, Isao
Watanabe, Satoshi
Kikuchi, Toshiaki
Miura, Satoru
Tanaka, Hiroshi
Kitazaki, Takeshi
Yamaguchi, Hiroyuki
Mukae, Hiroshi
Uchino, Junji
Uehara, Hisanori
Takayama, Koichi
Yano, Seiji
AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells
title AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells
title_full AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells
title_fullStr AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells
title_full_unstemmed AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells
title_short AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells
title_sort axl confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335418/
https://www.ncbi.nlm.nih.gov/pubmed/30651547
http://dx.doi.org/10.1038/s41467-018-08074-0
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