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

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. SulmanWebster K. Cavenee, Richard D. Kolodner, Clark C. Chen, Frank B. Furnari

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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 languageEnglish (US)
Pages (from-to)504-518.e7
JournalCancer Cell
Volume35
Issue number3
DOIs
StatePublished - Mar 18 2019

Bibliographical note

Funding Information:
We thank David James, Frederick Lang, Cameron Brennan, Paul Mischel, and Harley Kornblum for GBM-PDX neurospheres. We thank Daniel Gerlich for providing Ki-67 constructs, David Shcherbakova and Vladislav Verkhusha for providing iRFP720 plasmid, Kevin Corbett, Andrew Shiau, Arshad Desai, T.K., Amy Haseley Thorne, Nathan Jameson, Alison Parisian, and Afsheen Banisadr for helpful discussions and advice on figure layout, and Beata Mierzwa for illustration of the graphical abstract. This work was supported by the Defeat GBM Research Collaborative, a subsidiary of the National Brain Tumor Society (F.B.F., J.D.), the James S. McDonnell Foundation (F.B.F.), the National Institutes of Health ( R01-NS080939 (F.B.F.), R01-GM26017 (R.D.K.), 5R01-GM116897 (H.Z.), P50-CA127001 (E.P.S.), RO1-NS097649 (C.C.C)), PO1-HL107150 (N.M.V.), the Ludwig Institute for Cancer Research (F.B.F., H.Z., R.D.K, T.C.G., A.S.), the Doris Duke Charitable Foundation Clinical Scientist Development Award, The Sontag Foundation Distinguished Scientist Award, the Kimmel Scholar Award, and BWF 1006774.01 (C.C.C). L.O. was supported by the Lawski Foundation . The authors acknowledge the computational resources from Swedish National Infrastructure for Computing (SNIC 2016/34–40). Tissue Technology Shared Resource is supported by National Cancer Institute Cancer Center Support Grant (CCSG grant P30CA23100 )

Funding Information:
H&E and TUNEL staining: Tissues from mice were prepared and fixed in Formalin for 24 hr and transferred to 70% ethanol. H&E and TUNEL staining were performed and analyzed at the UCSD Tissue Technology Core, a shared resource supported by an NCI Cancer Center Support Grant (CCSG Grant P30CA23100).

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • DNA damage
  • FGFR2
  • GBM
  • PTEN
  • ionizing radiation (IR)
  • tyrosine phosphorylation

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