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Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair
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Number of Authors: 242019 (English)In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 35, no 3, p. 504-518.e7Article in journal (Refereed) Published
Abstract [en]

Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.

Place, publisher, year, edition, pages
2019. Vol. 35, no 3, p. 504-518.e7
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Cancer and Oncology Biological Sciences
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URN: urn:nbn:se:su:diva-167588DOI: 10.1016/j.ccell.2019.01.020ISI: 000461697400015PubMedID: 30827889OAI: oai:DiVA.org:su-167588DiVA, id: diva2:1301633
Available from: 2019-04-02 Created: 2019-04-02 Last updated: 2019-04-02Bibliographically approved

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Orellana, LauraKoga, TomoyukiLindahl, Erik
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