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Title: | Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance |
Author: | Alcón, Clara Manzano Muñoz, Albert Prada, Estela Mora Salvador, Jaume Soriano, Aroa Guillén, Gabriela Gallego, Soledad Roma, Josep Samitier i Martí, Josep Villanueva Garatachea, Alberto Montero, Joan |
Keywords: | Càncer en els infants Marcadors bioquímics Càncer en els adolescents Pronòstic mèdic Cancer in children Biochemical markers Cancer in adolescence Prognosis |
Issue Date: | 15-Aug-2020 |
Publisher: | Nature Publishing Group |
Abstract: | Rhabdomyosarcoma (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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1038/s41419-020-02887-y |
It is part of: | Cell Death and Disease, 2020, vol. 11(8), num. 634 |
URI: | http://hdl.handle.net/2445/174201 |
Related resource: | https://doi.org/10.1038/s41419-020-02887-y |
ISSN: | 2041-4889 |
Appears in Collections: | Articles publicats en revistes (Enginyeria Electrònica i Biomèdica) Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC)) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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