| Literature DB >> 30827889 |
Jianhui Ma1, Jorge A Benitez1, Jie Li2, Shunichiro Miki1, Claudio Ponte de Albuquerque1, Thais Galatro3, Laura Orellana4, Ciro Zanca1, Rachel Reed1, Antonia Boyer1, Tomoyuki Koga1, Nissi M Varki5, Tim R Fenton6, Suely Kazue Nagahashi Marie7, Erik Lindahl4, Timothy C Gahman1, Andrew K Shiau1, Huilin Zhou1, John DeGroot8, Erik P Sulman9, Webster K Cavenee10, Richard D Kolodner11, Clark C Chen2, Frank B Furnari12.
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. 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.Entities:
Keywords: DNA damage; FGFR2; GBM; PTEN; ionizing radiation (IR); tyrosine phosphorylation
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Year: 2019 PMID： 30827889 PMCID： PMC6424615 DOI： 10.1016/j.ccell.2019.01.020
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743