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  • 1.
    Ma, Jianhui
    et al.
    Univ Calif San Diego, Ludwig Inst Canc Res, San Diego Branch, 9500 Gilman Dr, La Jolla, CA 92093 USA. i, Jie; Cavenee, Webster K.; Kolodner, Richard D.; Chen, Clark C.; Furnari, Frank B..
    Benite, Jorge A.
    Miki, Shunichiro
    Albuquerqu, Claudio Ponte
    Galatro, Thais
    Orellana, Laura
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Zanca, Ciro
    Reed, Rachel
    Boyer, Antonia
    Koga, Tomoyuki
    Varki, Nissi M.
    Fenton, Tim R.
    Marie, Suely Kazue Nagahashi
    Lindahl, Erik
    KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Gahman, Timothy C.
    Shiau, Andrew K.
    Zhou, Huilin
    DeGroot, John
    Sulman, Erik P.
    Cavenee, Webster K.
    Kolodner, Richard D.
    Chen, Clark C.
    Furnari, Frank B.
    Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma diation Sensitivity through Attenuated DNA Repair2019In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 35, no 3, p. 504-518.e7Article in journal (Refereed)
    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.

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