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00925njm 22002777a 4500 dc Zhu, Lucía author Retana, Diana author García-Gómez, Pedro author Álvaro-Espinosa, Laura author Priego, Neibla author Masmudi-Martín, Mariam author Yebra, Natalia author Miarka, Lauritz author Hernández-Encinas, Elena author Blanco-Aparicio, Carmen author Martínez, Sonia author Sobrino, Cecilia author Ajenjo, Nuria author Artiga, Maria-Jesus author Ortega-Paino, Eva author Torres-Ruiz, Raúl author Rodríguez-Perales, Sandra author Soffietti, Riccardo author Bertero, Luca author Cassoni, Paola author Weiss, Tobias author Muñoz, Javier author Sepúlveda, Juan Manuel author González-León, Pedro author Jiménez-Roldán, Luis author Moreno, Luis Miguel author Esteban, Olga author Pérez-Núñez, Ángel author Hernández-Laín, Aurelio author Toldos, Oscar author Ruano, Yolanda author Alcázar, Lucía author Blasco, Guillermo author Fernández-Alén, José author Caleiras, Eduardo author Lafarga, Miguel author Megias Vazquez, Diego author Graña-Castro, Osvaldo author Nör, Carolina author Taylor, Michael D author Young, Leonie S author Varešlija, Damir author Cosgrove, Nicola author Couch, Fergus J author Cussó, Lorena author Desco, Manuel author Mouron, Silvana author Quintela-Fandino, Miguel author Weller, Michael author Pastor, Joaquín author Valiente, Manuel author 2022-03-07 We report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere. EMBO Mol Med. 2022 Mar 7;14(3):e14552 http://hdl.handle.net/20.500.12105/15688 35174975 10.15252/emmm.202114552 1757-4684 EMBO molecular medicine A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis.