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Título: | Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism |
Autor: | Monteiro, Cátia Miarka, Lauritz Perea-García, María Priego, Neibla García-Gómez, Pedro Álvaro-Espinosa, Laura de Pablos-Aragoneses, Ana Yebra, Natalia Retana, Diana Baena, Patricia Fustero-Torre, Coral Graña-Castro, Osvaldo Troulé, Kevin Caleiras, Eduardo Tezanos, Patricia Muela, Pablo Cintado, Elisa Trejo, José Luis Sepúlveda, Juan Manuel González-León, Pedro Jiménez-Roldán, Luis Moreno, Luis Miguel Esteban, Olga Pérez-Núñez, Ángel Hernández-Lain, Aurelio Mazarico Gallego, José Ferrer, Irene Suárez, Rocío Garrido-Martín, Eva M. Paz-Ares, Luis Dalmasso, Celine Cohen-Jonathan Moyal, Elizabeth Siegfried, Aurore Hegarty, Aisling Keelan, Stephen Varešlija, Damir Young, Leonie S. Mohme, Malte Goy, Yvonne Wikman, Harriet Fernández-Alén, Jose Blasco, Guillermo Alcázar, Lucía Cabañuz, Clara Grivennikov, Sergei I. Ianus, Andrada Shemesh, Noam Faria, Claudia Lee, Rebecca Lorigan, Paul Le Rhun, Emilie Weller, Michael Soffietti, Riccardo Bertero, Luca Ricardi, Umberto Bosch-Barrera, Joaquim Sais, Elia Teixidor, Eduard Hernández-Martínez, Alejandro Calvo, Alfonso Aristu, Javier Martin, Santiago M. Gonzalez, Alvaro Adler, Omer Erez, Neta Sobrino, Cecilia Ajenjo, Nuria Artiga, Maria-Jesus Ortega-Paino, Eva Valiente, Manuel |
Data: | 2022 |
Editora: | Springer Nature |
Citação: | Nat Med. 2022 Apr;28(4):752-765 |
Resumo: | Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity. |
Descrição: | © The Author(s) 2022. 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/. |
Peer review: | yes |
URI: | http://hdl.handle.net/10451/52536 |
DOI: | 10.1038/s41591-022-01749-8 |
ISSN: | 1078-8956 |
Versão do Editor: | https://www.nature.com/nm/ |
Aparece nas colecções: | FM - Artigos em Revistas Internacionais IMM - Artigos em Revistas Internacionais |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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Stratification_metastases.pdf | 2,66 MB | Adobe PDF | Ver/Abrir |
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