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.
Highlights
Glioblastoma (GBM) contains stem-like cells (GSCs) known to be resistant to ionizing radiation and responsible for therapeutic failure and rapidly lethal tumor recurrence
We investigated whether MET is a functional marker of GSC radioresistance, and whether MET could be exploited as a therapeutic target to achieve radiosensitization of GBM by depletion of its GSC component
We investigated whether patient-derived GSCs, propagated as NS, displayed greater radioresistance than non-stem/differentiated cells of the same lineage and whether radioresistance could be preferentially associated with specific genetic alterations or transcriptional profiles
Summary
Glioblastoma (GBM) contains stem-like cells (GSCs) known to be resistant to ionizing radiation and 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. We show that the MET receptor kinase, a functional marker of GSCs, is 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. Preclinical evidence is provided that MET inhibitors can radiosensitize tumors and convert GSC-positive selection, induced by radiotherapy, into GSC eradication
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