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.

Original languageEnglish
Pages (from-to)752-765
Number of pages14
JournalNature Medicine
Issue number4
StatePublished - Apr 2022


FundersFunder number
Champalimaud Centre for the UnknownLISBOA01-0145-FEDER-022170
ERC CoG864759
Foundation for Applied Cancer Research in Zurich
Fundació Roses Contra el Càncer
Fundação Millennium bcp
Girona Biomedical Research Institute
MICIN-Agencia Estatal de Investigación FellowshipsBES-2017-080415, PRE2020-093032
Ministerio de UniversidadesFPU 18/00069
Precision Oncology Ireland18/SPP/3522
Science Foundation Ireland Frontiers for the Future Award19/FFP/6443
Spanish National Biobanks Network
National Cancer InstituteR01 CA227629, R01CA218133
Cancer Research Institute54545
European Molecular Biology Organization
Fundación Ramón ArecesCIVP19S8163, CIVP20S10662
Fundació la Marató de TV3201906-30-31-32
Breast Cancer Now20/FFP-P/8597, 2019AugSF1310
Erich und Gertrud Roggenbuck-Stiftung
“la Caixa” Foundation100010434
Horizon 2020 Framework ProgrammeCF/BQ/PI20/11760029, 847648
Worldwide Cancer Research19-0177
Ministerio de Ciencia, Innovación y UniversidadesPID2019-110292RB-I00
Paradifference foundation
Science Foundation Ireland
Boehringer Ingelheim FondsPOSTD19016PRIE, LCF/BQ/DI17/11620028
Fundação para a Ciência e a TecnologiaSFRH/bd/100089/2014
Fundación Científica Asociación Española Contra el CáncerGCTRA16015SEOA
Ministerio de Economía y CompetitividadSAF2017-89643-R
Fundació Catalana de TrasplantamentPTDC/MED-ONC/32222/2017


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