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

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

Cancer cell (2019-03-05)

Jianhui Ma, Jorge A Benitez, Jie Li, Shunichiro Miki, Claudio Ponte de Albuquerque, Thais Galatro, Laura Orellana, Ciro Zanca, Rachel Reed, Antonia Boyer, Tomoyuki Koga, Nissi M Varki, Tim R Fenton, Suely Kazue Nagahashi Marie, Erik Lindahl, Timothy C Gahman, Andrew K Shiau, Huilin Zhou, John DeGroot, Erik P Sulman, Webster K Cavenee, Richard D Kolodner, Clark C Chen, Frank B Furnari

PMID30827889

RESUMEN

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.