mTOR inhibition induces compensatory, therapeutically targetable MEK activation in renal cell carcinoma.
Rapamycin derivatives allosterically targeting mTOR are currently FDA approved to treat advanced renal cell carcinoma (RCC), and catalytic inhibitors of mTOR/PI3K are now in clinical trials for treating various solid tumors. We sought to investigate the relative efficacy of allosteric versus catalyt...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4152178?pdf=render |
| _version_ | 1818317821957898240 |
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| author | Sean T Bailey Bing Zhou Jeffrey S Damrauer Bhavani Krishnan Harper L Wilson Aleisha M Smith Mingqing Li Jen Jen Yeh William Y Kim |
| author_facet | Sean T Bailey Bing Zhou Jeffrey S Damrauer Bhavani Krishnan Harper L Wilson Aleisha M Smith Mingqing Li Jen Jen Yeh William Y Kim |
| author_sort | Sean T Bailey |
| collection | DOAJ |
| description | Rapamycin derivatives allosterically targeting mTOR are currently FDA approved to treat advanced renal cell carcinoma (RCC), and catalytic inhibitors of mTOR/PI3K are now in clinical trials for treating various solid tumors. We sought to investigate the relative efficacy of allosteric versus catalytic mTOR inhibition, evaluate the crosstalk between the mTOR and MEK/ERK pathways, as well as the therapeutic potential of dual mTOR and MEK inhibition in RCC. Pharmacologic (rapamycin and BEZ235) and genetic manipulation of the mTOR pathway were evaluated by in vitro assays as monotherapy as well as in combination with MEK inhibition (GSK1120212). Catalytic mTOR inhibition with BEZ235 decreased proliferation and increased apoptosis better than allosteric mTOR inhibition with rapamycin. While mTOR inhibition upregulated MEK/ERK signaling, concurrent inhibition of both pathways had enhanced therapeutic efficacy. Finally, primary RCC tumors could be classified into subgroups [(I) MEK activated, (II) Dual MEK and mTOR activated, (III) Not activated, and (IV) mTOR activated] based on their relative activation of the PI3K/mTOR and MEK pathways. Patients with mTOR only activated tumors had the worst prognosis. In summary, dual targeting of the mTOR and MEK pathways in RCC can enhance therapeutic efficacy and primary RCC can be subclassified based on their relative levels of mTOR and MEK activation with potential therapeutic implications. |
| first_indexed | 2024-12-13T09:43:25Z |
| format | Article |
| id | doaj.art-eb8a1e11db0b49d6bd742dd26126b34c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T09:43:25Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-eb8a1e11db0b49d6bd742dd26126b34c2022-12-21T23:52:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0199e10441310.1371/journal.pone.0104413mTOR inhibition induces compensatory, therapeutically targetable MEK activation in renal cell carcinoma.Sean T BaileyBing ZhouJeffrey S DamrauerBhavani KrishnanHarper L WilsonAleisha M SmithMingqing LiJen Jen YehWilliam Y KimRapamycin derivatives allosterically targeting mTOR are currently FDA approved to treat advanced renal cell carcinoma (RCC), and catalytic inhibitors of mTOR/PI3K are now in clinical trials for treating various solid tumors. We sought to investigate the relative efficacy of allosteric versus catalytic mTOR inhibition, evaluate the crosstalk between the mTOR and MEK/ERK pathways, as well as the therapeutic potential of dual mTOR and MEK inhibition in RCC. Pharmacologic (rapamycin and BEZ235) and genetic manipulation of the mTOR pathway were evaluated by in vitro assays as monotherapy as well as in combination with MEK inhibition (GSK1120212). Catalytic mTOR inhibition with BEZ235 decreased proliferation and increased apoptosis better than allosteric mTOR inhibition with rapamycin. While mTOR inhibition upregulated MEK/ERK signaling, concurrent inhibition of both pathways had enhanced therapeutic efficacy. Finally, primary RCC tumors could be classified into subgroups [(I) MEK activated, (II) Dual MEK and mTOR activated, (III) Not activated, and (IV) mTOR activated] based on their relative activation of the PI3K/mTOR and MEK pathways. Patients with mTOR only activated tumors had the worst prognosis. In summary, dual targeting of the mTOR and MEK pathways in RCC can enhance therapeutic efficacy and primary RCC can be subclassified based on their relative levels of mTOR and MEK activation with potential therapeutic implications.http://europepmc.org/articles/PMC4152178?pdf=render |
| spellingShingle | Sean T Bailey Bing Zhou Jeffrey S Damrauer Bhavani Krishnan Harper L Wilson Aleisha M Smith Mingqing Li Jen Jen Yeh William Y Kim mTOR inhibition induces compensatory, therapeutically targetable MEK activation in renal cell carcinoma. PLoS ONE |
| title | mTOR inhibition induces compensatory, therapeutically targetable MEK activation in renal cell carcinoma. |
| title_full | mTOR inhibition induces compensatory, therapeutically targetable MEK activation in renal cell carcinoma. |
| title_fullStr | mTOR inhibition induces compensatory, therapeutically targetable MEK activation in renal cell carcinoma. |
| title_full_unstemmed | mTOR inhibition induces compensatory, therapeutically targetable MEK activation in renal cell carcinoma. |
| title_short | mTOR inhibition induces compensatory, therapeutically targetable MEK activation in renal cell carcinoma. |
| title_sort | mtor inhibition induces compensatory therapeutically targetable mek activation in renal cell carcinoma |
| url | http://europepmc.org/articles/PMC4152178?pdf=render |
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