MET inhibition overcomes radiation resistance of glioblastoma stem-like cells.
Glioblastoma (GBM) contains stem-like cells (GSCs) known to be resistant to ionizing radiation and thus responsible for therapeutic failure and rapidly lethal tumor recurrence. It is known that GSC radioresistance relies on efficient activation of the DNA damage response, but the mechanisms linking this response with the stem status are still unclear. Here, we show that the MET receptor kinase, a functional marker of GSCs, is specifically expressed in a subset of radioresistant GSCs and overexpressed in human GBM recurring after radiotherapy. We elucidate that MET promotes GSC radioresistance through a novel mechanism, relying on AKT activity and leading to (i) sustained activation of Aurora kinase A, ATM kinase, and the downstream effectors of DNA repair, and (ii) phosphorylation and cytoplasmic retention of p21, which is associated with anti-apoptotic functions. We show that MET pharmacological inhibition causes DNA damage accumulation in irradiated GSCs and their depletion in vitro and in GBMs generated by GSC xenotransplantation. Preclinical evidence is thus provided that MET inhibitors can radiosensitize tumors and convert GSC-positive selection, induced by radiotherapy, into GSC eradication.
['De Bacco|Francesca|F|', "D'Ambrosio|Antonio|A|", 'Casanova|Elena|E|', 'Orzan|Francesca|F|', 'Neggia|Roberta|R|', 'Albano|Raffaella|R|', 'Verginelli|Federica|F|', 'Cominelli|Manuela|M|', 'Poliani|Pietro L|PL|', 'Luraghi|Paolo|P|', 'Reato|Gigliola|G|', 'Pellegatta|Serena|S|', 'Finocchiaro|Gaetano|G|', 'Perera|Timothy|T|', 'Garibaldi|Elisabetta|E|', 'Gabriele|Pietro|P|', 'Comoglio|Paolo M|PM|', 'Boccaccio|Carla|C|0000-0003-2620-9083']
D000818:Animals D064007:Ataxia Telangiectasia Mutated Proteins D064096:Aurora Kinase A D002470:Cell Survival D050759:Cyclin-Dependent Kinase Inhibitor p21 D004260:DNA Repair D005909:Glioblastoma D064593:Heterografts D006801:Humans D051379:Mice D051058:Oncogene Protein v-akt D019859:Proto-Oncogene Proteins c-met D013234:Stem Cells
glioblastoma radiotherapy radiosensitization MET oncogene glioblastoma stem‐like cells