Cargando…

Activation of the mTOR Pathway by Oxaliplatin in the Treatment of Colorectal Cancer Liver Metastasis

BACKGROUND: Standard of care treatment for colorectal cancer liver metastasis consists of a cytotoxic chemotherapy in combination with a targeted agent. Clinical trials have guided the use of these combinatory therapies, but it remains unclear what the optimal combinations of cytotoxic chemotherapy...

Descripción completa

Detalles Bibliográficos
Autores principales: Lu, Min, Zessin, Amelia S., Glover, Wayne, Hsu, David S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5218497/
https://www.ncbi.nlm.nih.gov/pubmed/28060954
http://dx.doi.org/10.1371/journal.pone.0169439
_version_ 1782492293183307776
author Lu, Min
Zessin, Amelia S.
Glover, Wayne
Hsu, David S.
author_facet Lu, Min
Zessin, Amelia S.
Glover, Wayne
Hsu, David S.
author_sort Lu, Min
collection PubMed
description BACKGROUND: Standard of care treatment for colorectal cancer liver metastasis consists of a cytotoxic chemotherapy in combination with a targeted agent. Clinical trials have guided the use of these combinatory therapies, but it remains unclear what the optimal combinations of cytotoxic chemotherapy with a targeted agent are. METHODS: Using a genomic based approach, gene expression profiling was obtained from tumor samples of patient with colorectal cancer liver metastasis who received an oxaliplatin based therapy. Early passaged colorectal cancer liver metastasis cell lines and patient derived xenografts of colorectal cancer liver metastasis were then treated with oxaliplatin and a mTOR inhibitor. RESULTS: Gene set enrichment analysis revealed that the mTOR pathway was activated in patients receiving oxaliplatin based therapy. Treatment of early passaged colorectal cancer lines and patient derived xenografts with oxaliplatin resulted in activation of the mTOR pathway. Combination therapy with oxaliplatin and a mTOR inhibitor resulted in a synergistic effect both in vitro and in vivo. CONCLUSION: Our findings suggest a genomic based approach can be used to identify optimal combinations of cytotoxic chemotherapy with a targeted agent and that these observations can be validated both in vitro and in vivo using patient derived colorectal cancer cell lines and patient derived xenografts prior to clinical use.
format Online
Article
Text
id pubmed-5218497
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-52184972017-01-19 Activation of the mTOR Pathway by Oxaliplatin in the Treatment of Colorectal Cancer Liver Metastasis Lu, Min Zessin, Amelia S. Glover, Wayne Hsu, David S. PLoS One Research Article BACKGROUND: Standard of care treatment for colorectal cancer liver metastasis consists of a cytotoxic chemotherapy in combination with a targeted agent. Clinical trials have guided the use of these combinatory therapies, but it remains unclear what the optimal combinations of cytotoxic chemotherapy with a targeted agent are. METHODS: Using a genomic based approach, gene expression profiling was obtained from tumor samples of patient with colorectal cancer liver metastasis who received an oxaliplatin based therapy. Early passaged colorectal cancer liver metastasis cell lines and patient derived xenografts of colorectal cancer liver metastasis were then treated with oxaliplatin and a mTOR inhibitor. RESULTS: Gene set enrichment analysis revealed that the mTOR pathway was activated in patients receiving oxaliplatin based therapy. Treatment of early passaged colorectal cancer lines and patient derived xenografts with oxaliplatin resulted in activation of the mTOR pathway. Combination therapy with oxaliplatin and a mTOR inhibitor resulted in a synergistic effect both in vitro and in vivo. CONCLUSION: Our findings suggest a genomic based approach can be used to identify optimal combinations of cytotoxic chemotherapy with a targeted agent and that these observations can be validated both in vitro and in vivo using patient derived colorectal cancer cell lines and patient derived xenografts prior to clinical use. Public Library of Science 2017-01-06 /pmc/articles/PMC5218497/ /pubmed/28060954 http://dx.doi.org/10.1371/journal.pone.0169439 Text en © 2017 Lu et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Lu, Min
Zessin, Amelia S.
Glover, Wayne
Hsu, David S.
Activation of the mTOR Pathway by Oxaliplatin in the Treatment of Colorectal Cancer Liver Metastasis
title Activation of the mTOR Pathway by Oxaliplatin in the Treatment of Colorectal Cancer Liver Metastasis
title_full Activation of the mTOR Pathway by Oxaliplatin in the Treatment of Colorectal Cancer Liver Metastasis
title_fullStr Activation of the mTOR Pathway by Oxaliplatin in the Treatment of Colorectal Cancer Liver Metastasis
title_full_unstemmed Activation of the mTOR Pathway by Oxaliplatin in the Treatment of Colorectal Cancer Liver Metastasis
title_short Activation of the mTOR Pathway by Oxaliplatin in the Treatment of Colorectal Cancer Liver Metastasis
title_sort activation of the mtor pathway by oxaliplatin in the treatment of colorectal cancer liver metastasis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5218497/
https://www.ncbi.nlm.nih.gov/pubmed/28060954
http://dx.doi.org/10.1371/journal.pone.0169439
work_keys_str_mv AT lumin activationofthemtorpathwaybyoxaliplatininthetreatmentofcolorectalcancerlivermetastasis
AT zessinamelias activationofthemtorpathwaybyoxaliplatininthetreatmentofcolorectalcancerlivermetastasis
AT gloverwayne activationofthemtorpathwaybyoxaliplatininthetreatmentofcolorectalcancerlivermetastasis
AT hsudavids activationofthemtorpathwaybyoxaliplatininthetreatmentofcolorectalcancerlivermetastasis