AUTHOR=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 TITLE=MET Inhibition Sensitizes Rhabdomyosarcoma Cells to NOTCH Signaling Suppression JOURNAL=Frontiers in Oncology VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.835642 DOI=10.3389/fonc.2022.835642 ISSN=2234-943X 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.