List of communications


MET inhibition overcomes radiation resistance of glioblastoma stem-like cells

Francesca De Bacco, Candiolo Cancer Institute, FPO-IRCCS, University of Torino, Candiolo, Italy; Antonio D’Ambrosio, Candiolo Cancer Institute, FPO-IRCCS, University of Torino, Candiolo, Italy; Elena Casanova, Candiolo Cancer Institute, FPO-IRCCS, University of Torino, Candiolo, Italy; Francesca Orzan, Candiolo Cancer Institute, FPO-IRCCS, University of Torino, Candiolo, Italy; Roberta Neggia, Candiolo Cancer Institute, FPO-IRCCS, University of Torino, Candiolo, Italy; Raffaella Albano, Candiolo Cancer Institute, FPO-IRCCS, University of Torino, Candiolo, Italy; Federica Verginelli, Candiolo Cancer Institute, FPO-IRCCS, University of Torino, Candiolo, Italy; Paolo Luraghi, Candiolo Cancer Institute, FPO-IRCCS, University of Torino, Candiolo, Italy; Gigliola Reato, Candiolo Cancer Institute, FPO-IRCCS, University of Torino, Candiolo, Italy; Serena Pellegatta, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy; Gaetano Finocchiaro, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy; Timothy Perera, Octimet Oncology Ltd., Oxford, UK; Elisabetta Garibaldi, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy; Pietro Gabriele, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy; Paolo M. Comoglio, Candiolo Cancer Institute, FPO-IRCCS, University of Torino, Candiolo, Italy; Carla Boccaccio; Candiolo Cancer Institute, FPO-IRCCS, University of Torino, Candiolo, Italy.


Glioblastoma (GBM), the most aggressive and common type of primary brain tumor, often remains refractory to the best standard of care, integrating surgery, radiotherapy and chemotherapy. Primary resistance to DNA-damaging agents, mostly ionizing radiation, has been associated with inherent properties of the glioblastoma stem-like cell (GSC) subpopulation, but it relies on molecular mechanisms still poorly understood.We show that neurospheres (NS), i.e. culture enriched in GSCs, are significantly more radioresistant than their pseudo-differentiated counterpart, immortalized GBM cell lines, or normal astrocytes, independently of their mutational status and gene expression profile. Interestingly, in an ample subset of NS, radioresistance is distinctively associated with a cell subpopulation that expresses high levels of the HGF receptor MET, and retains stem-like properties. We show that the MET tyrosine kinase promotes GSC radioresistance by fostering the DNA-damage response through a signaling pathway involving Akt, which sustains DNA repair via ATM phosphorylation, and prevents apoptosis via p21 cytoplasmic retention. Pharmacological inhibition of MET impairs the mechanisms of GSC radioresistance. Accordingly, treatment of GBM generated by NS transplantation shows that MET inhibitors cooperate with radiotherapy in reducing tumor volume and prolonging mouse survival, and leads to exhaustion of the GSC tumorigenic subpopulation.

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