Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Monteiro, C. (Cátia); Miarka, L. (Lauritz); Perea-García, M. (María); Priego, N. (Neibla); García-Gómez, P. (Pedro); Álvaro-Espinosa, L. (Laura); de Pablos-Aragoneses, A. (Ana); Retana, D. (Diana); Baena, P. (Patricia); Fustero-Torre, C. (Coral); Graña-Castro, O. (Osvaldo); Troulé, K. (Kevin); Caleiras, E. (Eduardo); Tezanos, P. (Patricia); Muela, P. (Pablo); Cintado, E. (Elisa); Trejo, J.L. (José Luis); Sepúlveda, J.M. (Juan Manuel); González-León, P. (Pedro); Jiménez-Roldán, L. (Luis); Moreno, L.M. (Luis Miguel); Esteban, O. (Olga); Pérez-Núñez, A. (Ángel); Mazarico-Gallego, J. (José); Ferrer, I. (Irene); Suárez, R. (Rocío); Paz-Ares, L. (Luis); Siegfried, A. (Aurore); Hegarty, A. (Aisling); Aristu-Mendioroz, J.J. (José Javier)

Keywords:

Materias Investigacion::Ciencias de la Salud::Radiología
Radiosensitive brain metastases
S100A9/RAGE
Whole-brain radiotherapy
WBRT

Issue Date:

2022

Publisher:

Nature Research

ISSN:

1078-8956

Note:

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adap- tation, 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 statu- tory 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/. © The Author(s) 2022

Citation:

Monteiro, C. (Cátia); Miarka, L. (Lauritz); Perea-García, M. (María); et al. "Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism". Nature medicine. 28, 2022, 752 - 765

Abstract

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 understand- ing 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 mela- noma, 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.

URI:

https://hdl.handle.net/10171/69080

DOI:

10.1038/s41591-022-01749-8

Appears in Collections:

DA - CUN - Radiología - Artículos de revista

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