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A transcriptional MAPK Pathway Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types
KRAS- and BRAF-mutant tumors are often dependent on MAPK signaling for proliferation and survival and thus sensitive to MAPK pathway inhibitors. However, clinical studies have shown that MEK inhibitors are not uniformly effective in these cancers indicating that mutational status of these oncogenes...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871852/ https://www.ncbi.nlm.nih.gov/pubmed/29872725 http://dx.doi.org/10.1038/s41698-018-0051-4 |
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author | Wagle, Marie-Claire Kirouac, Daniel Klijn, Christiaan Liu, Bonnie Mahajan, Shilpi Junttila, Melissa Moffat, John Merchant, Mark Huw, Ling Wongchenko, Matthew Okrah, Kwame Srinivasan, Shrividhya Mounir, Zineb Sumiyoshi, Teiko Haverty, Peter M. Yauch, Robert L. Yan, Yibing Kabbarah, Omar Hampton, Garret Amler, Lukas Ramanujan, Saroja Lackner, Mark R. Huang, Shih-Min A. |
author_facet | Wagle, Marie-Claire Kirouac, Daniel Klijn, Christiaan Liu, Bonnie Mahajan, Shilpi Junttila, Melissa Moffat, John Merchant, Mark Huw, Ling Wongchenko, Matthew Okrah, Kwame Srinivasan, Shrividhya Mounir, Zineb Sumiyoshi, Teiko Haverty, Peter M. Yauch, Robert L. Yan, Yibing Kabbarah, Omar Hampton, Garret Amler, Lukas Ramanujan, Saroja Lackner, Mark R. Huang, Shih-Min A. |
author_sort | Wagle, Marie-Claire |
collection | PubMed |
description | KRAS- and BRAF-mutant tumors are often dependent on MAPK signaling for proliferation and survival and thus sensitive to MAPK pathway inhibitors. However, clinical studies have shown that MEK inhibitors are not uniformly effective in these cancers indicating that mutational status of these oncogenes does not accurately capture MAPK pathway activity. A number of transcripts are regulated by this pathway and are recurrently identified in genome-based MAPK transcriptional signatures. To test whether the transcriptional output of only 10 of these targets could quantify MAPK pathway activity with potential predictive or prognostic clinical utility, we created a MAPK Pathway Activity Score (MPAS) derived from aggregated gene expression. In vitro, MPAS predicted sensitivity to MAPK inhibitors in multiple cell lines, comparable to or better than larger genome-based statistical models. Bridging in vitro studies and clinical samples, median MPAS from a given tumor type correlated with cobimetinib (MEK inhibitor) sensitivity of cancer cell lines originating from the same tissue type. Retrospective analyses of clinical datasets showed that MPAS was associated with the sensitivity of melanomas to vemurafenib (HR: 0.596) and negatively prognostic of overall or progression-free survival in both adjuvant and metastatic CRC (HR: 1.5 and 1.4), adrenal cancer (HR: 1.7), and HER2+ breast cancer (HR: 1.6). MPAS thus demonstrates potential clinical utility that warrants further exploration. |
format | Online Article Text |
id | pubmed-5871852 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58718522018-06-05 A transcriptional MAPK Pathway Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types Wagle, Marie-Claire Kirouac, Daniel Klijn, Christiaan Liu, Bonnie Mahajan, Shilpi Junttila, Melissa Moffat, John Merchant, Mark Huw, Ling Wongchenko, Matthew Okrah, Kwame Srinivasan, Shrividhya Mounir, Zineb Sumiyoshi, Teiko Haverty, Peter M. Yauch, Robert L. Yan, Yibing Kabbarah, Omar Hampton, Garret Amler, Lukas Ramanujan, Saroja Lackner, Mark R. Huang, Shih-Min A. NPJ Precis Oncol Article KRAS- and BRAF-mutant tumors are often dependent on MAPK signaling for proliferation and survival and thus sensitive to MAPK pathway inhibitors. However, clinical studies have shown that MEK inhibitors are not uniformly effective in these cancers indicating that mutational status of these oncogenes does not accurately capture MAPK pathway activity. A number of transcripts are regulated by this pathway and are recurrently identified in genome-based MAPK transcriptional signatures. To test whether the transcriptional output of only 10 of these targets could quantify MAPK pathway activity with potential predictive or prognostic clinical utility, we created a MAPK Pathway Activity Score (MPAS) derived from aggregated gene expression. In vitro, MPAS predicted sensitivity to MAPK inhibitors in multiple cell lines, comparable to or better than larger genome-based statistical models. Bridging in vitro studies and clinical samples, median MPAS from a given tumor type correlated with cobimetinib (MEK inhibitor) sensitivity of cancer cell lines originating from the same tissue type. Retrospective analyses of clinical datasets showed that MPAS was associated with the sensitivity of melanomas to vemurafenib (HR: 0.596) and negatively prognostic of overall or progression-free survival in both adjuvant and metastatic CRC (HR: 1.5 and 1.4), adrenal cancer (HR: 1.7), and HER2+ breast cancer (HR: 1.6). MPAS thus demonstrates potential clinical utility that warrants further exploration. Nature Publishing Group UK 2018-03-07 /pmc/articles/PMC5871852/ /pubmed/29872725 http://dx.doi.org/10.1038/s41698-018-0051-4 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 Wagle, Marie-Claire Kirouac, Daniel Klijn, Christiaan Liu, Bonnie Mahajan, Shilpi Junttila, Melissa Moffat, John Merchant, Mark Huw, Ling Wongchenko, Matthew Okrah, Kwame Srinivasan, Shrividhya Mounir, Zineb Sumiyoshi, Teiko Haverty, Peter M. Yauch, Robert L. Yan, Yibing Kabbarah, Omar Hampton, Garret Amler, Lukas Ramanujan, Saroja Lackner, Mark R. Huang, Shih-Min A. A transcriptional MAPK Pathway Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types |
title | A transcriptional MAPK Pathway Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types |
title_full | A transcriptional MAPK Pathway Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types |
title_fullStr | A transcriptional MAPK Pathway Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types |
title_full_unstemmed | A transcriptional MAPK Pathway Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types |
title_short | A transcriptional MAPK Pathway Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types |
title_sort | transcriptional mapk pathway activity score (mpas) is a clinically relevant biomarker in multiple cancer types |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871852/ https://www.ncbi.nlm.nih.gov/pubmed/29872725 http://dx.doi.org/10.1038/s41698-018-0051-4 |
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