Sistema de Salut de Catalunya
Institut Català de la Salut
[Perrone C] Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy. Department of Science, “Department of Excellence 2018-2022”, University of Rome “Roma Tre”, Rome, Italy. [Pomella S, Pezzella M, Milano GM, Colletti M] Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy. [Cassandri M] Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy. Department of Radiotherapy, Sapienza University, Rome, Italy. [Roma J, Gallego S] Grup de Recerca Translacional en Càncer en la Infància i l’Adolescència, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain
Vall d'Hebron Barcelona Hospital Campus
2022-09-09T08:21:14Z
2022-09-09T08:21:14Z
2022-04-27
Drug resistance; Soft tissue sarcoma; Targeted therapy
Resistencia a las drogas; Sarcoma de tejido blando; Terapia dirigida
Resistència als fàrmacs; Sarcoma dels teixits tous; Teràpia dirigida
Rhabdomyosarcoma (RMS) is a pediatric myogenic soft tissue sarcoma. The Fusion-Positive (FP) subtype expresses the chimeric protein PAX3-FOXO1 (P3F) while the Fusion-Negative (FN) is devoid of any gene translocation. FP-RMS and metastatic FN-RMS are often unresponsive to conventional therapy. Therefore, novel therapeutic approaches are needed to halt tumor progression. NOTCH signaling has oncogenic functions in RMS and its pharmacologic inhibition through γ-secretase inhibitors blocks tumor growth in vitro and in vivo. Here, we show that NOTCH signaling blockade resulted in the up-regulation and phosphorylation of the MET oncogene in both RH30 (FP-RMS) and RD (FN-RMS) cell lines. Pharmacologic inhibition of either NOTCH or MET signaling slowed proliferation and restrained cell survival compared to control cells partly by increasing Annexin V and CASP3/7 activation. Co-treatment with NOTCH and MET inhibitors significantly amplified these effects and enhanced PARP1 cleavage in both cell lines. Moreover, it severely hampered cell migration, colony formation, and anchorage-independent growth compared to single-agent treatments in both cell lines and significantly prevented the growth of FN-RMS cells grown as spheroids. Collectively, our results unveil the overexpression of the MET oncogene by NOTCH signaling targeting in RMS cells and show that MET pathway blockade sensitizes them to NOTCH inhibition.
This research was funded by Associazione Italiana per la Ricerca sul Cancro (AIRC) #15312 to RR and #24696 to FM; Italian Ministry of Health (Ricerca Corrente) to BDA, CQ, and RR; AIRC 5xmille #9962 to FL; Italian Ministry of Health (Fondi 5xmille 2021-2022) to RR; Alleanza Contro il Cancro (ACC) Italian Network-Working Group Sarcomas to BDA, RM, and RR; Fondi Ateneo 2019 to FM; MIUR-Italy: Grant to Department of Science, Roma Tre University (Dipartimento di Eccellenza, ARTICOLO 1, COMMI 314—337 LEGGE 232/2016) to MCe and PM.
Article
Published version
English
Tumors de parts toves - Tractament; Pediatria; Proteïnes quinases - Inhibidors; DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Connective and Soft Tissue::Neoplasms, Muscle Tissue::Myosarcoma::Rhabdomyosarcoma; Other subheadings::Other subheadings::Other subheadings::/drug therapy; DISCIPLINES AND OCCUPATIONS::Health Occupations::Medicine::Pediatrics; CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors; ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de tejido conjuntivo y de tejidos blandos::neoplasias de tejido muscular::miosarcoma::rabdomiosarcoma; Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia; DISCIPLINAS Y OCUPACIONES::profesiones sanitarias::medicina::pediatría; COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas
Frontiers Media
Frontiers in Oncology;12
https://doi.org/10.3389/fonc.2022.835642
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Articles científics - VHIR [1655]
