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FOXO transcriptional activity is associated with response to chemoradiation in EAC
In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) rese...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9036728/ https://www.ncbi.nlm.nih.gov/pubmed/35468793 http://dx.doi.org/10.1186/s12967-022-03376-w |
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author | Creemers, A. van der Zalm, A. P. van de Stolpe, A. Holtzer, L. Stoffels, M. Hooijer, G. K. J. Ebbing, E. A. van Ooijen, H. van Brussel, A. G. C. Aussems-Custers, E. M. G. van Berge Henegouwen, M. I. Hulshof, M. C. C. M. Bergman, J. J. G. H. M. Meijer, S. L. Bijlsma, M. F. van Laarhoven, H. W. M. |
author_facet | Creemers, A. van der Zalm, A. P. van de Stolpe, A. Holtzer, L. Stoffels, M. Hooijer, G. K. J. Ebbing, E. A. van Ooijen, H. van Brussel, A. G. C. Aussems-Custers, E. M. G. van Berge Henegouwen, M. I. Hulshof, M. C. C. M. Bergman, J. J. G. H. M. Meijer, S. L. Bijlsma, M. F. van Laarhoven, H. W. M. |
author_sort | Creemers, A. |
collection | PubMed |
description | In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03376-w. |
format | Online Article Text |
id | pubmed-9036728 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-90367282022-04-26 FOXO transcriptional activity is associated with response to chemoradiation in EAC Creemers, A. van der Zalm, A. P. van de Stolpe, A. Holtzer, L. Stoffels, M. Hooijer, G. K. J. Ebbing, E. A. van Ooijen, H. van Brussel, A. G. C. Aussems-Custers, E. M. G. van Berge Henegouwen, M. I. Hulshof, M. C. C. M. Bergman, J. J. G. H. M. Meijer, S. L. Bijlsma, M. F. van Laarhoven, H. W. M. J Transl Med Research In this study we aimed to investigate signaling pathways that drive therapy resistance in esophageal adenocarcinoma (EAC). Paraffin-embedded material was analyzed in two patient cohorts: (i) 236 EAC patients with a primary tumor biopsy and corresponding post neoadjuvant chemoradiotherapy (nCRT) resection; (ii) 66 EAC patients with resection and corresponding recurrence. Activity of six key cancer-related signaling pathways was inferred using the Bayesian inference method. When assessing pre- and post-nCRT samples, lower FOXO transcriptional activity was observed in poor nCRT responders compared to good nCRT responders (p = 0.0017). This poor responder profile was preserved in recurrences compared to matched resections (p = 0.0007). PI3K pathway activity, inversely linked with FOXO activity, was higher in CRT poor responder cell lines compared to CRT good responders. Poor CRT responder cell lines could be sensitized to CRT using PI3K inhibitors. To conclude, by using a novel method to measure signaling pathway activity on clinically available material, we identified an association of low FOXO transcriptional activity with poor response to nCRT. Targeting this pathway sensitized cells for nCRT, underlining its feasibility to select appropriate targeted therapies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03376-w. BioMed Central 2022-04-25 /pmc/articles/PMC9036728/ /pubmed/35468793 http://dx.doi.org/10.1186/s12967-022-03376-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Creemers, A. van der Zalm, A. P. van de Stolpe, A. Holtzer, L. Stoffels, M. Hooijer, G. K. J. Ebbing, E. A. van Ooijen, H. van Brussel, A. G. C. Aussems-Custers, E. M. G. van Berge Henegouwen, M. I. Hulshof, M. C. C. M. Bergman, J. J. G. H. M. Meijer, S. L. Bijlsma, M. F. van Laarhoven, H. W. M. FOXO transcriptional activity is associated with response to chemoradiation in EAC |
title | FOXO transcriptional activity is associated with response to chemoradiation in EAC |
title_full | FOXO transcriptional activity is associated with response to chemoradiation in EAC |
title_fullStr | FOXO transcriptional activity is associated with response to chemoradiation in EAC |
title_full_unstemmed | FOXO transcriptional activity is associated with response to chemoradiation in EAC |
title_short | FOXO transcriptional activity is associated with response to chemoradiation in EAC |
title_sort | foxo transcriptional activity is associated with response to chemoradiation in eac |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9036728/ https://www.ncbi.nlm.nih.gov/pubmed/35468793 http://dx.doi.org/10.1186/s12967-022-03376-w |
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