Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism
Cátia Monteiro1, Lauritz Miarka1, María Perea-García1, Neibla Priego1, Pedro García-Gómez1, Laura Álvaro-Espinosa1, Ana de Pablos-Aragoneses1, Natalia Yebra1, Diana Retana1, Patricia Baena1, Coral Fustero-Torre2, Osvaldo Graña-Castro2, Kevin Troulé2, Eduardo Caleiras3, Patricia Tezanos4, Pablo Muela4, Elisa Cintado4, José Luis Trejo4, Juan Manuel Sepúlveda5, Pedro González-León6, Luis Jiménez-Roldán6,7, Luis Miguel Moreno6, Olga Esteban6, Ángel Pérez-Núñez6,7, Aurelio Hernández-Lain8, José Mazarico Gallego9, Irene Ferrer10,11, Rocío Suárez10,11, Eva M Garrido-Martín10,11, Luis Paz-Ares9,10,11,12, Celine Dalmasso13, Elizabeth Cohen-Jonathan Moyal13, Aurore Siegfried14, Aisling Hegarty15, Stephen Keelan15, Damir Varešlija15, Leonie S Young15, Malte Mohme16, Yvonne Goy17, Harriet Wikman18, Jose Fernández-Alén19, Guillermo Blasco19, Lucía Alcázar19, Clara Cabañuz20, Sergei I Grivennikov21,22, Andrada Ianus23, Noam Shemesh23, Claudia C Faria24,25, Rebecca Lee26,27, Paul Lorigan26,27, Emilie Le Rhun28, Michael Weller28, Riccardo Soffietti29, Luca Bertero30, Umberto Ricardi31, Joaquim Bosch-Barrera32,33,34, Elia Sais32,33, Eduard Teixidor32,33, Alejandro Hernández-Martínez32,33, Alfonso Calvo11,35, Javier Aristu36, Santiago M Martin37, Alvaro Gonzalez38, Omer Adler39, Neta Erez39, RENACER, Manuel Valiente40
- Brain Metastasis Group, CNIO, Madrid, Spain.
- Bioinformatics Unit, CNIO, Madrid, Spain.
- Histopathology Core Unit, CNIO, Madrid, Spain.
- Department of Translational Neuroscience, Cajal Institute, CSIC, Madrid, Spain.
- Neuro-Oncology Unit, Hospital Universitario 12 de Octubre, Madrid, Spain.
- Neurosurgery Unit, Hospital Universitario 12 de Octubre, Madrid, Spain.
- Department of Surgery, Universidad Complutense de Madrid, Madrid, Spain.
- Neuropathology Unit, Hospital Universitario 12 de Octubre, Madrid, Spain.
- Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
- CNIO-H12O Clinical Cancer Research Unit, Fundación de Investigación Biomédica i+12 and CNIO, Madrid, Spain.
- CIBERONC.
- Department of Medicine, Universidad Complutense de Madrid, Madrid, Spain.
- Radiation Oncology Department, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
- Anatomopathology Department, CHU Toulouse, IUCT-Oncopole, Toulouse, France.
- Endocrine Oncology Research Group, RCSI University of Medicine and Health Sciences, Dublin, Ireland.
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Radiation Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Neurosurgery, Hospital Universitario de La Princesa, Madrid, Spain.
- Department of Pathology, Hospital Universitario La Paz, Madrid, Spain.
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal.
- Instituto de Medicina Molecular João Lobo Antunes, Facultade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
- Department of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte (CHULN), Lisboa, Portugal.
- Faculty of Biology Medicine and Health, The University of Manchester, Manchester, UK.
- The Christie NHS Foundation Trust, Manchester, UK.
- Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
- Division of Neuro-Oncology, Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy.
- Department of Medical Sciences, University of Turin, Turin, Italy.
- Department of Oncology, University of Turin, Turin, Italy.
- Department of Medical Oncology, Catalan Institute of Oncology, Doctor Josep Trueta University Hospital, Girona, Spain.
- Girona Biomedical Research Institute (IDIBGi), Salt, Spain.
- Department of Medical Sciences, University of Girona, Girona, Spain.
- IDISNA, Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
- Department of Oncology, University Clinic of Navarra, Madrid, Spain.
- Department of Oncology, University Clinic of Navarra, Pamplona, Spain.
- Department of Biochemistry, University Clinic of Navarra, Pamplona, Spain.
- Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
- Brain Metastasis Group, CNIO, Madrid, Spain. mvaliente@cnio.es.
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 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.
Presented By Lauritz Miarka