Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance
Por:
Alcon C, Manzano-Muñoz A, Prada-Varela E, Mora J, Soriano A, Guillén G, Gallego S, Roma J, Samitier J, Villanueva A and Montero J
Publicada:
15 ago 2020
Ahead of Print:
15 ago 2020
Resumen:
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.
Filiaciones:
Alcon C:
Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain
Manzano-Muñoz A:
Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain
Prada-Varela E:
Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, 08950, Esplugues de Llobregat, Spain
Department of Haematology and Oncology, Hospital Sant Joan de Déu Barcelona, 08950, Esplugues de Llobregat, Spain
Mora J:
Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, 08950, Esplugues de Llobregat, Spain
Department of Haematology and Oncology, Hospital Sant Joan de Déu Barcelona, 08950, Esplugues de Llobregat, Spain
Soriano A:
Group of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035, Barcelona, Spain
Guillén G:
Group of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035, Barcelona, Spain
Department of Surgery, Universitat Autònoma de Barcelona (UAB), 08193, Barcelona, Spain
Gallego S:
Group of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035, Barcelona, Spain
Roma J:
Group of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), 08035, Barcelona, Spain
Samitier J:
Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain
Department of Electronics and Biomedical Engineering, University of Barcelona (UB), 08028, Barcelona, Spain
Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029, Madrid, Spain
Villanueva A:
Program against Cancer Therapeutic Resistance (ProCURE), IDIBELL, Catalan Institute of Oncology, l'Hospitalet del Llobregat, 08907, Barcelona, Spain
Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, l'Hospitalet de Llobregat, 08907, Barcelona, Spain
Montero J:
Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain.
Green Published, gold
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