title: MET inhibition overcomes radiation resistance of glioblastoma stem-like cells.
abstract: 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.
authors.affiliation: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Bacco
authors.affiliation: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy Department of Oncology, University of Torino, Candiolo, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Ambrosio
authors.affiliation: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Casanova
authors.affiliation: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Orzan
authors.affiliation: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Neggia
authors.affiliation: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Albano
authors.affiliation: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Verginelli
authors.affiliation: Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Cominelli
authors.affiliation: Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia, Italy.
authors.forename: Pietro L
authors.initials: PL
authors.lastname: Poliani
authors.affiliation: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Luraghi
authors.affiliation: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy Department of Oncology, University of Torino, Candiolo, Italy.
authors.forename: Gigliola
authors.initials: G
authors.lastname: Reato
authors.affiliation: Unit of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pellegatta
authors.affiliation: Unit of Molecular Neuro-Oncology, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Finocchiaro
authors.affiliation: Octimet Oncology Ltd., Oxford, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Perera
authors.affiliation: Unit of Radiotherapy, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Garibaldi
authors.affiliation: Unit of Radiotherapy, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Gabriele
authors.affiliation: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy Department of Oncology, University of Torino, Candiolo, Italy direzione.scientifica@ircc.it carla.boccaccio@ircc.it.
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.affiliation: Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy Department of Oncology, University of Torino, Candiolo, Italy direzione.scientifica@ircc.it carla.boccaccio@ircc.it.
authors.forename: Carla
authors.identifier: 0000-0003-2620-9083
authors.initials: C
authors.lastname: Boccaccio
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D064096:Aurora Kinase A / Q000378:metabolism; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004260:DNA Repair; D005909:Glioblastoma / Q000532:radiotherapy*; D064593:Heterografts; D006801:Humans; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D013234:Stem Cells / Q000502:physiology* / Q000528:radiation effects*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C576324:ATM protein, human; C576917:AURKA protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D064096:Aurora Kinase A; D051058:Oncogene Protein v-akt
keywords: MET oncogene; glioblastoma; glioblastoma stem‐like cells; radiosensitization; radiotherapy