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Cancer Cell. 2019 Mar 18;35(3):504-518.e7. doi: 10.1016/j.ccell.2019.01.020. Epub 2019 Feb 28.

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

Author information

1
Ludwig Institute for Cancer Research, San Diego Branch, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0660, USA.
2
Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA.
3
Department of Neurology, Laboratory of Molecular and Cellular Biology, LIM15, School of Medicine, University of São Paulo, São Paulo, Brazil.
4
Science for Life Laboratory, 17121 Stockholm, Sweden; Theoretical and Computational Biophysics, Department of Theoretical Physics, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden; Department of Biochemistry and Biophysics, Center for Biomembrane Research, Stockholm University, 114 18 Stockholm, Sweden.
5
Department of Pathology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
6
School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
7
Department of Neurology, Laboratory of Molecular and Cellular Biology, LIM15, School of Medicine, University of São Paulo, São Paulo, Brazil; Center for Studies of Cellular and Molecular Therapy (NAP-NETCEM-NUCEL), University of São Paulo, São Paulo, Brazil.
8
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
9
Departments of Radiation Oncology, Translational Molecular Pathology, and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
10
Ludwig Institute for Cancer Research, San Diego Branch, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0660, USA; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA; School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
11
Ludwig Institute for Cancer Research, San Diego Branch, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0660, USA; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA; Department of Cellular and Molecular Medicine, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
12
Ludwig Institute for Cancer Research, San Diego Branch, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0660, USA; Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, USA; Department of Pathology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address: ffurnari@ucsd.edu.

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.

KEYWORDS:

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

PMID:
30827889
PMCID:
PMC6424615
[Available on 2020-03-18]
DOI:
10.1016/j.ccell.2019.01.020

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