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

Brain Neoplasms / secondary Cranial Irradiation Humans Melanoma / radiotherapy

Journal

Nature medicine

ISSN: 1546-170X

Titre abrégé: Nat Med

Pays: United States

ID NLM: 9502015

Informations de publication

Date de publication:
04 2022

Historique:

received: 14 05 2021

accepted: 16 02 2022

pubmed: 13 4 2022

medline: 22 4 2022

entrez: 12 4 2022

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41591-022-01749-8 PMID: 35411077 PMC: PMC9018424

pubmed: 35411077

doi: 10.1038/s41591-022-01749-8

pii: 10.1038/s41591-022-01749-8

pmc: PMC9018424

doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

752-765

Subventions

Organisme : NCI NIH HHS

ID : R01 CA227629

Pays : United States

Organisme : NCI NIH HHS

ID : R01 CA218133

Pays : United States

Investigateurs

Cecilia Sobrino (C)

Nuria Ajenjo (N)

Maria-Jesus Artiga (MJ)

Eva Ortega-Paino (E)

Informations de copyright

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