mTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF.

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, is a critical problem in the treatment of EGFR mutant lung cancer. Several mechanisms, including bypass signaling by hepatocyte growth factor (HGF)-triggered Met activation, are implicated...

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Autores principales:	Daisuke Ishikawa, Shinji Takeuchi, Takayuki Nakagawa, Takako Sano, Junya Nakade, Shigeki Nanjo, Tadaaki Yamada, Hiromichi Ebi, Lu Zhao, Kazuo Yasumoto, Takahiro Nakamura, Kunio Matsumoto, Hiroshi Kagamu, Hirohisa Yoshizawa, Seiji Yano
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2a4ca02dcdca49eb800aab4aeeb60dfd
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spelling	oai:doaj.org-article:2a4ca02dcdca49eb800aab4aeeb60dfd2021-11-18T07:45:56ZmTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF.1932-620310.1371/journal.pone.0062104https://doaj.org/article/2a4ca02dcdca49eb800aab4aeeb60dfd2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23690929/?tool=EBIhttps://doaj.org/toc/1932-6203Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, is a critical problem in the treatment of EGFR mutant lung cancer. Several mechanisms, including bypass signaling by hepatocyte growth factor (HGF)-triggered Met activation, are implicated as mediators of resistance. The mammalian target of rapamycin (mTOR), is a downstream conduit of EGFR and MET signaling, and is thus considered a therapeutically attractive target in the treatment of various types of cancers. The purpose of this study was to examine whether 2 clinically approved mTOR inhibitors, temsirolimus and everolimus, overcome HGF-dependent resistance to EGFR-TKIs in EGFR mutant lung cancer cells. Both temsirolimus and everolimus inhibited the phosphorylation of p70S6K and 4E-BP1, which are downstream targets of the mTOR pathway, and reduced the viability of EGFR mutant lung cancer cells, PC-9, and HCC827, even in the presence of HGF in vitro. In a xenograft model, temsirolimus suppressed the growth of PC-9 cells overexpressing the HGF-gene; this was associated with suppression of the mTOR signaling pathway and tumor angiogenesis. In contrast, erlotinib did not suppress this signaling pathway or tumor growth. Multiple mechanisms, including the inhibition of vascular endothelial growth factor production by tumor cells and suppression of endothelial cell viability, contribute to the anti-angiogenic effect of temsirolimus. These findings indicate that mTOR inhibitors may be useful for controlling HGF-triggered EGFR-TKI resistance in EGFR mutant lung cancer, and they provide the rationale for clinical trials of mTOR inhibitors in patients stratified by EGFR mutation and HGF expression status.Daisuke IshikawaShinji TakeuchiTakayuki NakagawaTakako SanoJunya NakadeShigeki NanjoTadaaki YamadaHiromichi EbiLu ZhaoKazuo YasumotoTakahiro NakamuraKunio MatsumotoHiroshi KagamuHirohisa YoshizawaSeiji YanoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e62104 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Daisuke Ishikawa Shinji Takeuchi Takayuki Nakagawa Takako Sano Junya Nakade Shigeki Nanjo Tadaaki Yamada Hiromichi Ebi Lu Zhao Kazuo Yasumoto Takahiro Nakamura Kunio Matsumoto Hiroshi Kagamu Hirohisa Yoshizawa Seiji Yano mTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF.
description	Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, is a critical problem in the treatment of EGFR mutant lung cancer. Several mechanisms, including bypass signaling by hepatocyte growth factor (HGF)-triggered Met activation, are implicated as mediators of resistance. The mammalian target of rapamycin (mTOR), is a downstream conduit of EGFR and MET signaling, and is thus considered a therapeutically attractive target in the treatment of various types of cancers. The purpose of this study was to examine whether 2 clinically approved mTOR inhibitors, temsirolimus and everolimus, overcome HGF-dependent resistance to EGFR-TKIs in EGFR mutant lung cancer cells. Both temsirolimus and everolimus inhibited the phosphorylation of p70S6K and 4E-BP1, which are downstream targets of the mTOR pathway, and reduced the viability of EGFR mutant lung cancer cells, PC-9, and HCC827, even in the presence of HGF in vitro. In a xenograft model, temsirolimus suppressed the growth of PC-9 cells overexpressing the HGF-gene; this was associated with suppression of the mTOR signaling pathway and tumor angiogenesis. In contrast, erlotinib did not suppress this signaling pathway or tumor growth. Multiple mechanisms, including the inhibition of vascular endothelial growth factor production by tumor cells and suppression of endothelial cell viability, contribute to the anti-angiogenic effect of temsirolimus. These findings indicate that mTOR inhibitors may be useful for controlling HGF-triggered EGFR-TKI resistance in EGFR mutant lung cancer, and they provide the rationale for clinical trials of mTOR inhibitors in patients stratified by EGFR mutation and HGF expression status.
format	article
author	Daisuke Ishikawa Shinji Takeuchi Takayuki Nakagawa Takako Sano Junya Nakade Shigeki Nanjo Tadaaki Yamada Hiromichi Ebi Lu Zhao Kazuo Yasumoto Takahiro Nakamura Kunio Matsumoto Hiroshi Kagamu Hirohisa Yoshizawa Seiji Yano
author_facet	Daisuke Ishikawa Shinji Takeuchi Takayuki Nakagawa Takako Sano Junya Nakade Shigeki Nanjo Tadaaki Yamada Hiromichi Ebi Lu Zhao Kazuo Yasumoto Takahiro Nakamura Kunio Matsumoto Hiroshi Kagamu Hirohisa Yoshizawa Seiji Yano
author_sort	Daisuke Ishikawa
title	mTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF.
title_short	mTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF.
title_full	mTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF.
title_fullStr	mTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF.
title_full_unstemmed	mTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF.
title_sort	mtor inhibitors control the growth of egfr mutant lung cancer even after acquiring resistance by hgf.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/2a4ca02dcdca49eb800aab4aeeb60dfd
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mTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF.

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