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mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential

Metastasis is the biggest challenge in treating breast cancer, and it kills >40,000 breast cancer patients annually in the US. Aberrant expression of the RON receptor tyrosine kinase in breast tumors correlates with poor prognosis and has been shown to promote metastasis. However, the molecular m...

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Autores principales: Faham, Najme, Zhao, Ling, Welm, Alana L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226524/
https://www.ncbi.nlm.nih.gov/pubmed/30456298
http://dx.doi.org/10.1038/s41523-018-0091-5
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author Faham, Najme
Zhao, Ling
Welm, Alana L.
author_facet Faham, Najme
Zhao, Ling
Welm, Alana L.
author_sort Faham, Najme
collection PubMed
description Metastasis is the biggest challenge in treating breast cancer, and it kills >40,000 breast cancer patients annually in the US. Aberrant expression of the RON receptor tyrosine kinase in breast tumors correlates with poor prognosis and has been shown to promote metastasis. However, the molecular mechanisms that govern how RON promotes metastasis, and how to block it, are still largely unknown. We sought to determine critical effectors of RON using a combination of mutational and pharmacologic strategies. High-throughput proteomic analysis of breast cancer cells upon activation of RON showed robust phosphorylation of ribosomal protein S6. Further analysis revealed that RON strongly signals through mTORC1/p70S6K, which is mediated predominantly by the PI3K pathway. A targeted mutation approach to modulate RON signaling validated the importance of PI3K/mTORC1 pathway for spontaneous metastasis in vivo. Finally, inhibition of mTORC1 with an FDA-approved drug, everolimus, resulted in transient shrinkage of established RON-dependent metastases, and combined blockade of mTORC1 and RON delayed progression. These studies have identified a key downstream mediator of RON-dependent metastasis in breast cancer cells and revealed that inhibition of mTORC1, or combined inhibition of mTORC1 and RON, may be effective for treatment of metastatic breast cancers with elevated expression of RON.
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spelling pubmed-62265242018-11-19 mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential Faham, Najme Zhao, Ling Welm, Alana L. NPJ Breast Cancer Article Metastasis is the biggest challenge in treating breast cancer, and it kills >40,000 breast cancer patients annually in the US. Aberrant expression of the RON receptor tyrosine kinase in breast tumors correlates with poor prognosis and has been shown to promote metastasis. However, the molecular mechanisms that govern how RON promotes metastasis, and how to block it, are still largely unknown. We sought to determine critical effectors of RON using a combination of mutational and pharmacologic strategies. High-throughput proteomic analysis of breast cancer cells upon activation of RON showed robust phosphorylation of ribosomal protein S6. Further analysis revealed that RON strongly signals through mTORC1/p70S6K, which is mediated predominantly by the PI3K pathway. A targeted mutation approach to modulate RON signaling validated the importance of PI3K/mTORC1 pathway for spontaneous metastasis in vivo. Finally, inhibition of mTORC1 with an FDA-approved drug, everolimus, resulted in transient shrinkage of established RON-dependent metastases, and combined blockade of mTORC1 and RON delayed progression. These studies have identified a key downstream mediator of RON-dependent metastasis in breast cancer cells and revealed that inhibition of mTORC1, or combined inhibition of mTORC1 and RON, may be effective for treatment of metastatic breast cancers with elevated expression of RON. Nature Publishing Group UK 2018-11-09 /pmc/articles/PMC6226524/ /pubmed/30456298 http://dx.doi.org/10.1038/s41523-018-0091-5 Text en © The Author(s) 2018 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
Faham, Najme
Zhao, Ling
Welm, Alana L.
mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential
title mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential
title_full mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential
title_fullStr mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential
title_full_unstemmed mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential
title_short mTORC1 is a key mediator of RON-dependent breast cancer metastasis with therapeutic potential
title_sort mtorc1 is a key mediator of ron-dependent breast cancer metastasis with therapeutic potential
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226524/
https://www.ncbi.nlm.nih.gov/pubmed/30456298
http://dx.doi.org/10.1038/s41523-018-0091-5
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