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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, Shunichiro;
- de Albuquerque, Claudio Ponte;
- Galatro, Thais;
- Orellana, Laura;
- Zanca, Ciro;
- Reed, Rachel;
- Boyer, Antonia;
- Koga, Tomoyuki;
- Varki, Nissi M;
- Fenton, Tim R;
- Marie, Suely Kazue Nagahashi;
- Lindahl, Erik;
- 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
- et al.
Published Web Location
https://doi.org/10.1016/j.ccell.2019.01.020Abstract
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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