MEK and MCL-1 sequential inhibition synergize to enhance rhabdomyosarcoma treatment
Por:
Alcon C, Martín F, Prada-Varela E, Mora J, Soriano A, Guillén G, Gallego S, Roma J, Samitier J, Villanueva A and Montero J
Publicada:
7 abr 2022
Ahead of Print:
7 abr 2022
Resumen:
Targeted agents have emerged as promising molecules for cancer treatment, but most of them fail to achieve complete tumor regression or attain durable remissions due to tumor adaptations. We used dynamic BH3 profiling to identify targeted agents effectiveness and anti-apoptotic adaptations upon targeted treatment in rhabdomyosarcoma. We focused on studying the use of BH3 mimetics to specifically inhibit pro-survival BCL-2 family proteins, overwhelm resistance to therapy and prevent relapse. We observed that the MEK1/2 inhibitor trametinib rapidly depleted the pro-apoptotic protein NOXA, thus increasing MCL-1 availability. Indeed, we found that the MCL-1 inhibitor S63845 synergistically enhanced trametinib cytotoxicity in rhabdomyosarcoma cells in vitro and in vivo. In conclusion, our findings indicate that the combination of a BH3 mimetic targeting MCL-1 with trametinib improves efficiency on rhabdomyosarcoma by blocking tumor adaptation to treatment.
Filiaciones:
Alcon C:
Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain
Martín F:
Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain
Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029, Madrid, Spain
Prada-Varela E:
Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de Déu, 08950, Esplugues de Llobregat, Spain
Pediatric Cancer Center Barcelona (PCCB), 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
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
Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029, Madrid, Spain
Department of Electronics and Biomedical Engineering, University of Barcelona (UB), 08028, Barcelona, Spain
Villanueva A:
Program against Cancer Therapeutic Resistance (ProCURE), IDIBELL, Catalan Institute of Oncology, 08907 l'Hospitalet del Llobregat, Barcelona, Spain
Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, 08907 l'Hospitalet de Llobregat, Barcelona, Spain
Montero J:
Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain.
Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029, Madrid, Spain.
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