Citation

  • Authors: Ma, J., Benitez, J. A., Li, J., Miki, S., Ponte de Albuquerque, C., Galatro, T., Orellana, L., Zanca, C., Reed, R., Boyer, A., Koga, T., Varki, N. M., Fenton, T. R., Nagahashi Marie, S. K., Lindahl, E., Gahman, T. C., Shiau, A. K., Zhou, H., DeGroot, J., Sulman, E. P., Cavenee, W. K., Kolodner, R. D., Chen, C. C., Furnari, F. B.
  • Year: 2019
  • Journal: Cancer Cell 35 504-518 e7
  • Applications: in vitro / Protein/Peptide/Antibody / PULSin
  • Cell type: HEK-293T
    Description: Human embryonic kidney Fibroblast
    Known as: HEK293T, 293T

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.

Pubmed