Finding effective treatment options for patients with brain metastasis remains an unmet need. Given the limitations imposed by the blood-brain-barrier for systemic approaches, radiotherapy offers a superior ability to access the brain. While whole-brain-radiation-therapy (WBRT) historically has been the gold standard in the management of brain metastasis patients, clinical practice rapidly adapted the frequent use of stereotactic radiosurgery (SRS), given the high incidence of neurotoxicity when giving WBRT. However, WBRT continuous to be an important treatment option, since many patients present with numerous multifocal lesions, high risk of SRS-associated radionecrosis, bad performance scores or probable distant intracranial recurrence, rendering them ineligible for SRS. Unfortunately, overall survival of patients remains unaffected by radiotherapy. In spite of this clinical data, the underlying molecular mechanisms that allow metastatic cells to resist radiotherapy in the brain is unknown. We have applied WBRT to experimental brain metastasis from lung and breast adenocarcinoma and validated their resistance in vivo. An unbiased search to identify potential mediators of resistance identified the S100A9-RAGE-NFkB-JunB pathway. Targeting this pathway genetically reverts the resistance to radiotherapy and increases therapeutic benefits in vivo. In two independent cohorts of brain metastasis from lung and breast adenocarcinoma patients, levels of S100A9 correlate with the response to radiotherapy, offering a novel approach to stratify patients according to their expected benefit. As a proof of concept, we also detected S100A9 in serum and CSF samples from brain metastasis patients, complementing our biomarker strategy with a less invasive approach. Furthermore, we have validated the use of a blood-brain-barrier permeable RAGE inhibitor to restore radio-sensitivity in experimental brain metastasis models in vivo and in patient-derived organotypic cultures of radio-resistant brain metastasis ex vivo. In conclusion, we identified S100A9 as a major mediator of radio-resistance in brain metastasis and offer the molecular framework to personalize radiotherapy by exploiting it as a biomarker and as a therapeutic target, thus maximizing the benefits for the patient.

Citation Format: Lauritz Miarka, Catia Monteiro, Celine Dalmasso, Natalia Yebra, Coral Fustero-Torre, Aisling Hegarty, Stephen Keelan, Eduardo Caleiras, Vareslija Damir, Leonie Young, Riccardo Soffietti, Juan M. Sepúlveda, Angel Pérez, Aurelio Lain, Aurore Siegfied, Elizabeth Cohen-Jonathan Moyal, Manuel Valiente. S100A9 mediates radiation resistance of brain metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-068.