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.
Original language | English (US) |
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Pages (from-to) | 504-518.e7 |
Journal | Cancer Cell |
Volume | 35 |
Issue number | 3 |
DOIs | |
State | Published - Mar 18 2019 |
Bibliographical note
Publisher Copyright:© 2019 Elsevier Inc.
Keywords
- DNA damage
- FGFR2
- GBM
- PTEN
- ionizing radiation (IR)
- tyrosine phosphorylation