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...
| Main Authors: | , , , , , , , , , , , , , , |
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| 格式: | 文件 |
| 语言: | English |
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Public Library of Science (PLoS)
2013-01-01
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| 丛编: | PLoS ONE |
| 在线阅读: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23690929/?tool=EBI |
| _version_ | 1829486235034320896 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T23:01:59Z |
| format | Article |
| id | doaj.art-2a4ca02dcdca49eb800aab4aeeb60dfd |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T23:01:59Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-2a4ca02dcdca49eb800aab4aeeb60dfd2022-12-21T22:44:25ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0185e6210410.1371/journal.pone.0062104mTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF.Daisuke IshikawaShinji TakeuchiTakayuki NakagawaTakako SanoJunya NakadeShigeki NanjoTadaaki YamadaHiromichi EbiLu ZhaoKazuo YasumotoTakahiro NakamuraKunio MatsumotoHiroshi KagamuHirohisa YoshizawaSeiji YanoResistance 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23690929/?tool=EBI |
| spellingShingle | 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. PLoS ONE |
| title | 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_short | 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 |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23690929/?tool=EBI |
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