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

Publication date: Apr 11, 2022

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-_705B-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.

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Concepts Keywords
Benefits Radiation therapy
Organ Radiation
Radiotherapy Brain metastasis
S100a9 S100A9
Whole brain radiotherapy
Clinical medicine


Type Source Name
drug DRUGBANK Deoxy-2-Fluoro-B-D-Cellotrioside
drug DRUGBANK Licofelone
drug DRUGBANK Pidolic Acid
disease MESH shock
drug DRUGBANK Aspartame
drug DRUGBANK Chloride ion
disease MESH separation
drug DRUGBANK Water
disease MESH Anxiety
drug DRUGBANK Acetic acid
drug DRUGBANK Ethanol
drug DRUGBANK Spinosad
drug DRUGBANK Dimethyl sulfoxide
pathway KEGG Glioma
disease MESH glioma
disease MESH immobilization
drug DRUGBANK Tricyclazole
drug DRUGBANK Isoflurane
disease MESH glioblastoma
pathway KEGG Breast cancer
disease MESH breast cancer
drug DRUGBANK Pentaerythritol tetranitrate
disease MESH lung adenocarcinoma
disease MESH lung cancer
drug DRUGBANK Naproxen
drug DRUGBANK Coenzyme M
disease MESH noma
disease MESH recurrences
drug DRUGBANK Gold
disease MESH diagnosis
disease MESH tic
disease MESH tumors
pathway KEGG Melanoma
disease MESH melanoma
disease MESH disease progression
disease MESH metastasis
disease MESH brain metastases

Original Article

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