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Identification of synthetic chemosensitivity genes paired with BRAF for BRAF/MAPK inhibitors
Molecular-targeted approaches are important for personalised cancer treatment, which requires knowledge regarding drug target specificity. Here, we used the synthetic lethality concept to identify candidate gene pairs with synergistic effects on drug responses. A synergistic chemo-sensitivity respon...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672081/ https://www.ncbi.nlm.nih.gov/pubmed/33203961 http://dx.doi.org/10.1038/s41598-020-76909-2 |
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author | Lee, Kye Hwa Goh, Jinmin Kim, Yi-Jun Kim, Kwangsoo |
author_facet | Lee, Kye Hwa Goh, Jinmin Kim, Yi-Jun Kim, Kwangsoo |
author_sort | Lee, Kye Hwa |
collection | PubMed |
description | Molecular-targeted approaches are important for personalised cancer treatment, which requires knowledge regarding drug target specificity. Here, we used the synthetic lethality concept to identify candidate gene pairs with synergistic effects on drug responses. A synergistic chemo-sensitivity response was identified if a drug had a significantly lower half-maximal inhibitory concentration (IC(50)) in cell lines with a pair of mutated genes compared with those in other cell lines (wild-type or one mutated gene). Among significantly damaging mutations in the Genomics of Drug Sensitivity in Cancer database, we found 580 candidate synergistic chemo-sensitivity interaction sets for 456 genes and 54 commercial drugs. Clustering analyses according to drug/gene and drug/tissue interactions showed that BRAF/MAPK inhibitors clustered together; 11 partner genes for BRAF were identified. The combined effects of these partners on IC(50) values were significant for both drug-specific and drug-combined comparisons. Survival analysis using The Cancer Genome Atlas data showed that patients who had mutated gene pairs in synergistic interaction sets had longer overall survival compared with that in patients with other mutation profiles. Overall, this analysis demonstrated that synergistic drug-responsive gene pairs could be successfully used as predictive markers of drug sensitivity and patient survival, offering new targets for personalised medicine. |
format | Online Article Text |
id | pubmed-7672081 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76720812020-11-18 Identification of synthetic chemosensitivity genes paired with BRAF for BRAF/MAPK inhibitors Lee, Kye Hwa Goh, Jinmin Kim, Yi-Jun Kim, Kwangsoo Sci Rep Article Molecular-targeted approaches are important for personalised cancer treatment, which requires knowledge regarding drug target specificity. Here, we used the synthetic lethality concept to identify candidate gene pairs with synergistic effects on drug responses. A synergistic chemo-sensitivity response was identified if a drug had a significantly lower half-maximal inhibitory concentration (IC(50)) in cell lines with a pair of mutated genes compared with those in other cell lines (wild-type or one mutated gene). Among significantly damaging mutations in the Genomics of Drug Sensitivity in Cancer database, we found 580 candidate synergistic chemo-sensitivity interaction sets for 456 genes and 54 commercial drugs. Clustering analyses according to drug/gene and drug/tissue interactions showed that BRAF/MAPK inhibitors clustered together; 11 partner genes for BRAF were identified. The combined effects of these partners on IC(50) values were significant for both drug-specific and drug-combined comparisons. Survival analysis using The Cancer Genome Atlas data showed that patients who had mutated gene pairs in synergistic interaction sets had longer overall survival compared with that in patients with other mutation profiles. Overall, this analysis demonstrated that synergistic drug-responsive gene pairs could be successfully used as predictive markers of drug sensitivity and patient survival, offering new targets for personalised medicine. Nature Publishing Group UK 2020-11-17 /pmc/articles/PMC7672081/ /pubmed/33203961 http://dx.doi.org/10.1038/s41598-020-76909-2 Text en © The Author(s) 2020 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Lee, Kye Hwa Goh, Jinmin Kim, Yi-Jun Kim, Kwangsoo Identification of synthetic chemosensitivity genes paired with BRAF for BRAF/MAPK inhibitors |
title | Identification of synthetic chemosensitivity genes paired with BRAF for BRAF/MAPK inhibitors |
title_full | Identification of synthetic chemosensitivity genes paired with BRAF for BRAF/MAPK inhibitors |
title_fullStr | Identification of synthetic chemosensitivity genes paired with BRAF for BRAF/MAPK inhibitors |
title_full_unstemmed | Identification of synthetic chemosensitivity genes paired with BRAF for BRAF/MAPK inhibitors |
title_short | Identification of synthetic chemosensitivity genes paired with BRAF for BRAF/MAPK inhibitors |
title_sort | identification of synthetic chemosensitivity genes paired with braf for braf/mapk inhibitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672081/ https://www.ncbi.nlm.nih.gov/pubmed/33203961 http://dx.doi.org/10.1038/s41598-020-76909-2 |
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