Alcón, ClaraManzano Muñoz, AlbertPrada, EstelaMora Salvador, JaumeSoriano, AroaGuillén, GabrielaGallego, SoledadRoma, JosepSamitier i Martí, JosepVillanueva Garatachea, AlbertoMontero, Joan2021-02-232021-02-232020-08-152041-4889https://hdl.handle.net/2445/174201Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. Refractory/relapsed RMS patients present a bad prognosis that combined with the lack of specific biomarkers impairs the development of new therapies. Here, we utilize dynamic BH3 profiling (DBP), a functional predictive biomarker that measures net changes in mitochondrial apoptotic signaling, to identify anti-apoptotic adaptations upon treatment. We employ this information to guide the use of BH3 mimetics to specifically inhibit BCL-2 pro-survival proteins, defeat resistance and avoid relapse. Indeed, we found that BH3 mimetics that selectively target anti-apoptotic BCL-xL and MCL-1, synergistically enhance the effect of clinically used chemotherapeutic agents vincristine and doxorubicin in RMS cells. We validated this strategy in vivo using a RMS patient-derived xenograft model and observed a reduction in tumor growth with a tendency to stabilization with the sequential combination of vincristine and the MCL-1 inhibitor S63845. We identified the molecular mechanism by which RMS cells acquire resistance to vincristine: an enhanced binding of BID and BAK to MCL-1 after drug exposure, which is suppressed by subsequently adding S63845. Our findings validate the use of DBP as a functional assay to predict treatment effectiveness in RMS and provide a rationale for combining BH3 mimetics with chemotherapeutic agents to avoid tumor resistance, improve treatment efficiency, and decrease undesired secondary effects.13 p.application/pdfengcc-by-nc-sa (c) Alcón, Clara et al., 2020http://creativecommons.org/licenses/by-nc-sa/3.0/esCàncer en els infantsMarcadors bioquímicsCàncer en els adolescentsPronòstic mèdicCancer in childrenBiochemical markersCancer in adolescencePrognosisinfo:eu-repo/semantics/article7060882021-02-23info:eu-repo/semantics/openAccess32801295