Abstract 2065: Targeting the crosstalk between MET and Notch signaling in Rhabdomyosarcoma

Abstract

Abstract Rhabdomyosarcoma (RMS) in a pediatric soft tissue sarcoma expressing myogenic markers. RMS includes two histological subtypes, embryonal and alveolar, which differ clinically and molecularly. The majority of alveolar RMS expresses fusion oncoproteins such as PAX3/7-FOXO1. Fusion positive (FP) RMS are at high risk showing a dismal prognosis while fusion negative (FN) ones have a better outcome. The MET protooncogene is a target gene of PAX3-FOXO1 and is overexpressed in FP RMS. However, it is upregulated/overactivated in FN RMS as well. It concurs to disease pathogenesis and is a potential target of therapy. We have shown that MET is down-regulated by the myomiR cluster miR-1/206 that promotes myogenic-like differentiation and inhibits proliferation of RMS cells. Notch signaling is also deregulated in RMS and inhibition of either Notch1 in FN or Notch3 in both subtypes leads to tumor growth blockade. Some preliminary data from our lab indicate that the expression of miR-1/206 is induced in Notch3-silenced RMS cells. Therefore, we sought to investigate the crosstalk between MET and Notch signaling in RMS. We detected a down-regulation of MET transcript and protein in Notch3 knocked down RMS cells. In turn, MET silencing reduced Notch1 and Notch3 activation together with the levels of Notch ligands, JAG1 and DLL1. In line with this, forced expression of an activated form of MET (Tpr) resulted in Notch1 over-activation and up-regulation in FN RMS cells. Notably, a FN cell line treated for long time (more than 6 months) with growing doses of EMD, a clinically relevant MET inhibitor, showed resistance to treatment, over-activation of MET, i.e., hyperphosphorylation, and Notch1 signaling hyperactivation. These preliminary results suggest that MET and Notch signaling could crosstalk in RMS and that their co-targeting could be used to overcome drug resistance to single agent therapy. To this end, combination treatments of MET inhibitors with clinically relevant gamma-secretase inhibitors are in course. The work is supported by Associazione Italiana Ricerca sul Cancro project IG15312 to RR. Citation Format: Rossella Rota, Cristina Cossetti, Silvia Pomella, Alberto Gualtieri, Elena Carcarino, Carola Ponzetto, Riccardo Taulli, Lucio Miele, Franco Locatelli. Targeting the crosstalk between MET and Notch signaling in Rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2065. doi:10.1158/1538-7445.AM2017-2065