Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair

• Published in: Cancer cell Vol. 35; no. 3; pp. 504 - 518.e7
• Main Authors: Ma, Jianhui, Benitez, Jorge A., Li, Jie, Miki, Shunichiro, Ponte de Albuquerque, Claudio, Galatro, Thais, Orellana, Laura, Zanca, Ciro, Reed, Rachel, Boyer, Antonia, Koga, Tomoyuki, Varki, Nissi M., Fenton, Tim R., Nagahashi Marie, Suely Kazue, 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.03.2019
• Subjects: Animals; Brain Neoplasms - metabolism; Brain Neoplasms - therapy; Cell Nucleus - metabolism; DNA damage; DNA Repair - drug effects; Female; FGFR2; GBM; Glioma - metabolism; Glioma - therapy; Humans; ionizing radiation (IR); Male; Mice; Phosphorylation - drug effects; PTEN; PTEN Phosphohydrolase - metabolism; Pyrimidines - administration & dosage; Pyrimidines - pharmacology; Rad51 Recombinase - metabolism; Radiation Tolerance - drug effects; Receptor, Fibroblast Growth Factor, Type 2 - metabolism; Tyrosine - metabolism; tyrosine phosphorylation; Xenograft Model Antitumor Assays; PTEN; GBM; ionizing radiation (IR); tyrosine phosphorylation; DNA damage; FGFR2
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2019.01.020

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. [Display omitted] •Phosphorylation of PTEN at tyrosine 240 (pY240) by FGFR2 mediates IR resistance•pY240-PTEN plays a critical role in DNA damage repair•pY240-PTEN associates with chromatin DNA through interaction with Ki-67•Blocking pY240-PTEN using FGFR inhibitors sensitizes tumors to ionizing radiation Ma et al. show that ionizing irradiation (IR) induces PTEN Y240 phosphorylation (pY240-PTEN) by FGFR2 in glioblastoma (GBM) cells. pY240-PTEN binds to chromatin and recruits RAD51 to promote DNA repair. Inhibition of Y240 phosphorylation sensitizes GBM to IR and prolongs the survival of GBM preclinical models.