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Towards pathway-centric cancer therapies via pharmacogenomic profiling analysis of ERK signalling pathway

BACKGROUND: Genomic heterogeneity in human cancers complicates gene-centric personalized medicine. Malignant tumors often share a core group of pathways that are perturbed by diverse genetic mutations. Therefore, one possible solution to overcome the heterogeneity challenge is a shift from gene-cent...

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Autores principales: Wang, Haiyun, Zheng, Xiaoqi, Fei, Teng, Wang, Jinzeng, Li, Xujuan, Liu, Yin, Zhang, Fan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518023/
https://www.ncbi.nlm.nih.gov/pubmed/26220863
http://dx.doi.org/10.1186/s40169-015-0066-1
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author Wang, Haiyun
Zheng, Xiaoqi
Fei, Teng
Wang, Jinzeng
Li, Xujuan
Liu, Yin
Zhang, Fan
author_facet Wang, Haiyun
Zheng, Xiaoqi
Fei, Teng
Wang, Jinzeng
Li, Xujuan
Liu, Yin
Zhang, Fan
author_sort Wang, Haiyun
collection PubMed
description BACKGROUND: Genomic heterogeneity in human cancers complicates gene-centric personalized medicine. Malignant tumors often share a core group of pathways that are perturbed by diverse genetic mutations. Therefore, one possible solution to overcome the heterogeneity challenge is a shift from gene-centric to pathway-centric therapies. Pathway-centric perspectives, which underscore the need to understand key pathways and their critical properties, could address the complexity of cancer heterogeneity better than gene-centric approaches to aid cancer drug discovery and therapy. METHODS: We used large-scale pharmacogenomic profiling data provided by the Cancer Genome Project of the Wellcome Trust Sanger Institute and the Cancer Cell Line Encyclopedia. In a systematic in silico investigation of ERK signalling pathway components and topological structures determines their influences on pathway activity and targeted therapies. Mann–Whitney U test was used to identify gene alterations associated with drug sensitivity with p values and Benjamini–Hochberg correction for multiple hypotheses testing. RESULTS: The analysis demonstrated that genetic alterations were crucial to activation of effector pathway and subsequent tumorigenesis, however drug sensitivity suffered from both drug effector and non-effector pathways, which were determined by not only underlying genomic alterations, but also interplay and topological relationship of components in pathway, suggesting that the combinatorial targets of key nodes in perturbed pathways may yield better treatment outcome. Furthermore, we proposed a model to provide a more comprehensive insight and understanding of pathway-centric cancer therapies. CONCLUSIONS: Our study provides a holistic view of factors influencing drug sensitivity and sheds light on pathway-centric cancer therapies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40169-015-0066-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-45180232015-08-03 Towards pathway-centric cancer therapies via pharmacogenomic profiling analysis of ERK signalling pathway Wang, Haiyun Zheng, Xiaoqi Fei, Teng Wang, Jinzeng Li, Xujuan Liu, Yin Zhang, Fan Clin Transl Med Research BACKGROUND: Genomic heterogeneity in human cancers complicates gene-centric personalized medicine. Malignant tumors often share a core group of pathways that are perturbed by diverse genetic mutations. Therefore, one possible solution to overcome the heterogeneity challenge is a shift from gene-centric to pathway-centric therapies. Pathway-centric perspectives, which underscore the need to understand key pathways and their critical properties, could address the complexity of cancer heterogeneity better than gene-centric approaches to aid cancer drug discovery and therapy. METHODS: We used large-scale pharmacogenomic profiling data provided by the Cancer Genome Project of the Wellcome Trust Sanger Institute and the Cancer Cell Line Encyclopedia. In a systematic in silico investigation of ERK signalling pathway components and topological structures determines their influences on pathway activity and targeted therapies. Mann–Whitney U test was used to identify gene alterations associated with drug sensitivity with p values and Benjamini–Hochberg correction for multiple hypotheses testing. RESULTS: The analysis demonstrated that genetic alterations were crucial to activation of effector pathway and subsequent tumorigenesis, however drug sensitivity suffered from both drug effector and non-effector pathways, which were determined by not only underlying genomic alterations, but also interplay and topological relationship of components in pathway, suggesting that the combinatorial targets of key nodes in perturbed pathways may yield better treatment outcome. Furthermore, we proposed a model to provide a more comprehensive insight and understanding of pathway-centric cancer therapies. CONCLUSIONS: Our study provides a holistic view of factors influencing drug sensitivity and sheds light on pathway-centric cancer therapies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40169-015-0066-1) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2015-07-28 /pmc/articles/PMC4518023/ /pubmed/26220863 http://dx.doi.org/10.1186/s40169-015-0066-1 Text en © Wang et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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.
spellingShingle Research
Wang, Haiyun
Zheng, Xiaoqi
Fei, Teng
Wang, Jinzeng
Li, Xujuan
Liu, Yin
Zhang, Fan
Towards pathway-centric cancer therapies via pharmacogenomic profiling analysis of ERK signalling pathway
title Towards pathway-centric cancer therapies via pharmacogenomic profiling analysis of ERK signalling pathway
title_full Towards pathway-centric cancer therapies via pharmacogenomic profiling analysis of ERK signalling pathway
title_fullStr Towards pathway-centric cancer therapies via pharmacogenomic profiling analysis of ERK signalling pathway
title_full_unstemmed Towards pathway-centric cancer therapies via pharmacogenomic profiling analysis of ERK signalling pathway
title_short Towards pathway-centric cancer therapies via pharmacogenomic profiling analysis of ERK signalling pathway
title_sort towards pathway-centric cancer therapies via pharmacogenomic profiling analysis of erk signalling pathway
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518023/
https://www.ncbi.nlm.nih.gov/pubmed/26220863
http://dx.doi.org/10.1186/s40169-015-0066-1
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