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Inhibition of nuclear PTEN tyrosine phosphorylation enhances glioma radiation sensitivity through attenuated DNA repair

Ma, Jianhui, Benitez, Jorge A, Li, Jie, Miki, Sunichiro, Ponte de Alberquerque, Claudio, Galatro, Thais, Orellana, Laura, Zanca, Ciro, Reed, Rachel, Boyer, Antonia, and others. (2019) Inhibition of nuclear PTEN tyrosine phosphorylation enhances glioma radiation sensitivity through attenuated DNA repair. Cancer Cell, . ISSN 1535-6108. (doi:10.1016/j.ccell.2019.01.020) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided)

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Abstract

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. Y240FPten knock-in 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.

Item Type: Article
DOI/Identification number: 10.1016/j.ccell.2019.01.020
Uncontrolled keywords: PTEN, tyrosine phosphorylation, FGFR2, GBM, ionizing radiation (IR), DNA damage
Subjects: Q Science
R Medicine
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Tim Fenton
Date Deposited: 04 Mar 2019 10:15 UTC
Last Modified: 30 May 2019 08:51 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/72083 (The current URI for this page, for reference purposes)
Fenton, TR: https://orcid.org/0000-0002-4737-8233
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