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 Sulman; Webster K Cavenee; Richard D Kolodner; Clark C Chen; Frank B Furnari

doi:10.1016/j.ccell.2019.01.020

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

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

Authors

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

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Neoplasms / metabolism
Brain Neoplasms / therapy*
Cell Nucleus / metabolism*
DNA Repair / drug effects
Female
Glioma / metabolism
Glioma / therapy*
Humans
Male
Mice
PTEN Phosphohydrolase / metabolism*
Phosphorylation / drug effects
Pyrimidines / administration & dosage*
Pyrimidines / pharmacology
Rad51 Recombinase / metabolism
Radiation Tolerance / drug effects*
Receptor, Fibroblast Growth Factor, Type 2 / metabolism*
Tyrosine / metabolism
Xenograft Model Antitumor Assays

Substances

PD 173074
Pyrimidines
Tyrosine
FGFR2 protein, human
Receptor, Fibroblast Growth Factor, Type 2
RAD51 protein, human
Rad51 Recombinase
PTEN Phosphohydrolase
PTEN protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding