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http://hdl.handle.net/2445/174201
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DC Field | Value | Language |
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dc.contributor.author | Alcón, Clara | - |
dc.contributor.author | Manzano Muñoz, Albert | - |
dc.contributor.author | Prada, Estela | - |
dc.contributor.author | Mora Salvador, Jaume | - |
dc.contributor.author | Soriano, Aroa | - |
dc.contributor.author | Guillén, Gabriela | - |
dc.contributor.author | Gallego, Soledad | - |
dc.contributor.author | Roma, Josep | - |
dc.contributor.author | Samitier i Martí, Josep | - |
dc.contributor.author | Villanueva Garatachea, Alberto | - |
dc.contributor.author | Montero, Joan | - |
dc.date.accessioned | 2021-02-23T11:06:02Z | - |
dc.date.available | 2021-02-23T11:06:02Z | - |
dc.date.issued | 2020-08-15 | - |
dc.identifier.issn | 2041-4889 | - |
dc.identifier.uri | http://hdl.handle.net/2445/174201 | - |
dc.description.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. | - |
dc.format.extent | 13 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Nature Publishing Group | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.1038/s41419-020-02887-y | - |
dc.relation.ispartof | Cell Death and Disease, 2020, vol. 11(8), num. 634 | - |
dc.relation.uri | https://doi.org/10.1038/s41419-020-02887-y | - |
dc.rights | cc-by-nc-sa (c) Alcón, Clara et al., 2020 | - |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/3.0/es | - |
dc.source | Articles publicats en revistes (Enginyeria Electrònica i Biomèdica) | - |
dc.subject.classification | Càncer en els infants | - |
dc.subject.classification | Marcadors bioquímics | - |
dc.subject.classification | Càncer en els adolescents | - |
dc.subject.classification | Pronòstic mèdic | - |
dc.subject.other | Cancer in children | - |
dc.subject.other | Biochemical markers | - |
dc.subject.other | Cancer in adolescence | - |
dc.subject.other | Prognosis | - |
dc.title | Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 706088 | - |
dc.date.updated | 2021-02-23T11:06:02Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 32801295 | - |
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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706088.pdf | 1.33 MB | Adobe PDF | View/Open |
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