Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance
Alcon, Clara (Institut de Bioenginyeria de Catalunya)
Manzano-Muñoz, Albert (Institut de Bioenginyeria de Catalunya)
Prada, Estela (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Català-Mora, Jaume (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Soriano, Aroa (Hospital Universitari Vall d'Hebron)
Guillén, Gabriela (Hospital Universitari Vall d'Hebron)
Gallego, Soledad (Hospital Universitari Vall d'Hebron)
Roma, Josep (Hospital Universitari Vall d'Hebron)
Samitier, Josep (Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina)
Villanueva, Alberto (Institut d'Investigació Biomèdica de Bellvitge)
Montero, Joan (Institut de Bioenginyeria de Catalunya)
Universitat Autònoma de Barcelona

Date:	2020
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.
Grants:	Ministerio de Economía y Competitividad RD16/0006/0012 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017 SGR 1079 Ministerio de Economía y Competitividad RYC-2015-18357
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Paediatric cancer ; Predictive markers
Published in:	Cell death and disease, Vol. 11 (august 2020) , ISSN 2041-4889

DOI: 10.1038/s41419-020-02887-y
PMID: 32801295

13 p, 1.3 MB

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