MET Inhibition Sensitizes Rhabdomyosarcoma Cells to NOTCH Signaling Suppression
Perrone, Clara (University of Rome)
Pomella, Silvia (Bambino Gesù Children's Hospital)
Cassandri, Matteo (Università degli Studi di Roma "La Sapienza")
Pezzella, Michele (Bambino Gesù Children's Hospital)
Milano, Giuseppe Maria (Bambino Gesù Children's Hospital)
Colletti, Marta (Bambino Gesù Children's Hospital)
Cossetti, Cristina (Bambino Gesù Children's Hospital)
Pericoli, Giulia (Bambino Gesù Children's Hospital)
Di Giannatale, Angela (Bambino Gesù Children's Hospital)
de Billy, Emmanuel (Bambino Gesù Children's Hospital)
Vinci, Maria (Bambino Gesù Children's Hospital)
Petrini, Stefania (Bambino Gesù Children's Hospital)
Marampon, Francesco (Università degli Studi di Roma "La Sapienza")
Quintarelli, Concetta (University of Naples Federico II)
Taulli, Riccardo (University of Torino)
Roma, Josep (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Gallego, Soledad (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Camero, Simona (University of Rome)
Mariottini, Paolo (University of Rome)
Cervelli, Manuela (University of Rome)
Maestro, Roberta (National Cancer Institute)
Miele, Lucio (Louisiana State University Health Sciences Center)
De Angelis, Biagio (Bambino Gesù Children's Hospital)
Locatelli, Franco (Università degli Studi di Roma "La Sapienza")
Rota, Rossella (Bambino Gesù Children's Hospital)
Universitat Autònoma de Barcelona

Date:	2022
Abstract:	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.
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:	Combination therapy ; Drug resistance ; MET ; NOTCH signaling ; Rhabdomyosarcoma ; Soft tissue sarcoma ; Targeted therapy ; Γ-secretase
Published in:	Frontiers in Oncology, Vol. 12 (april 2022) , ISSN 2234-943X

DOI: 10.3389/fonc.2022.835642
PMID: 35574376

16 p, 11.9 MB

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