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

Ma J, Benitez JA, Li J, Miki S, Ponte de Albuquerque C, Galatro T, Orellana L, Zanca C, Reed R, Boyer A, Koga T, Varki NM, Fenton TR, Nagahashi Marie SK, Lindahl E, Gahman TC, Shiau AK, Zhou H, DeGroot J, Sulman EP, Cavenee WK, Kolodner RD, Chen CC, Furnari FB

Cancer Cell 35 (3) 504-518.e7 [2019-03-18; online 2019-02-28]

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.

PubMed 30827889

DOI 10.1016/j.ccell.2019.01.020

Crossref 10.1016/j.ccell.2019.01.020

mid: NIHMS1520516
pmc: PMC6424615
pii: S1535-6108(19)30054-6