MET inhibition sensitizes rhabdomyosarcoma cells to NOTCH signaling suppression
| Autor: | Clara Perrone, Silvia Pomella, Matteo Cassandri, Michele Pezzella, Giuseppe Maria Milano, Marta Colletti, Cristina Cossetti, Giulia Pericoli, Angela Di Giannatale, Emmanuel de Billy, Maria Vinci, Stefania Petrini, Francesco Marampon, Concetta Quintarelli, Riccardo Taulli, Josep Roma, Soledad Gallego, Simona Camero, Paolo Mariottini, Manuela Cervelli, Roberta Maestro, Lucio Miele, Biagio De Angelis, Franco Locatelli, Rossella Rota |
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| Přispěvatelé: | 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, Perrone, Clara, Pomella, Silvia, Cassandri, Matteo, Pezzella, Michele, Milano, Giuseppe Maria, Colletti, Marta, Cossetti, Cristina, Pericoli, Giulia, Di Giannatale, Angela, de Billy, Emmanuel, Vinci, Maria, Petrini, Stefania, Marampon, Francesco, Quintarelli, Concetta, Taulli, Riccardo, Roma, Josep, Gallego, Soledad, Camero, Simona, Mariottini, Paolo, Cervelli, Manuela, Maestro, Roberta, Miele, Lucio, De Angelis, Biagio, Locatelli, Franco, Rota, Rossella |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Cancer Research
Pediatria drug resistance MET NOTCH signaling combination therapy rhabdomyosarcoma soft tissue sarcoma targeted therapy γ-secretase acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas [COMPUESTOS QUÍMICOS Y DROGAS] Health Occupations::Medicine::Pediatrics [DISCIPLINES AND OCCUPATIONS] Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] Other subheadings::Other subheadings::/drug therapy [Other subheadings] neoplasias::neoplasias por tipo histológico::neoplasias de tejido conjuntivo y de tejidos blandos::neoplasias de tejido muscular::miosarcoma::rabdomiosarcoma [ENFERMEDADES] Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors [CHEMICALS AND DRUGS] Settore MED/05 Tumors de parts toves - Tractament Proteïnes quinases - Inhibidors Oncology Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA Neoplasms::Neoplasms by Histologic Type::Neoplasms Connective and Soft Tissue::Neoplasms Muscle Tissue::Myosarcoma::Rhabdomyosarcoma [DISEASES] profesiones sanitarias::medicina::pediatría [DISCIPLINAS Y OCUPACIONES] |
| Zdroj: | Scientia |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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