Inhibition of nuclear PTEN tyrosine phosphorylation enhances glioma radiation sensitivity through attenuated DNA repair

Ma, Jianhui, Benitez, Jorge A, Li, Jie, Miki, Sunichiro, Alberquerque, Claudio Ponte de, Galatro, Thais, Orellana, Laura, Zanca, Ciro, Reed, Rachel, Boyer, Antonia, Koga, Tomoyuki, Varki, Nissi M, Fenton, TR, Marie, SK, Lindahl, Erik, Gahman, Timothy C., Shiau, Andrew K., Zhou, Huilin, deGroot, John, Sulman, Erik P., Cavenee, Webster K., Kolodner, Richard D., Chen, Clark C. and Furnari, FB (2019) Inhibition of nuclear PTEN tyrosine phosphorylation enhances glioma radiation sensitivity through attenuated DNA repair. Cancer Cell, 35 (3), 504-518. (doi:10.1016/j.ccell.2019.01.020).

Abstract

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. Y240FPten knock-in 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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Contributors

Author: TR Fenton

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