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

Autor:	Huilin Zhou, John DeGroot, Erik P. Sulman, Frank B. Furnari, Andrew K. Shiau, Webster K. Cavenee, Ciro Zanca, Shunichiro Miki, Timothy C. Gahman, Laura Orellana, Rachel Reed, Suely Kazue Nagahashi Marie, Clark C. Chen, Jianhui Ma, Thais F. Galatro, Richard D. Kolodner, Jorge A. Benitez, Claudio P. Albuquerque, Jie Li, Tomoyuki Koga, Erik Lindahl, Nissi Varki, Antonia D. Boyer, Tim R. Fenton
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	0301 basic medicine Male PTEN Cancer Research Fibroblast Growth Factor DNA Repair Radiation Tolerance chemistry.chemical_compound Mice 0302 clinical medicine Radiation sensitivity Phosphorylation health care economics and organizations Cancer biology Brain Neoplasms Glioma humanities Chromatin medicine.anatomical_structure Oncology 6.1 Pharmaceuticals 030220 oncology & carcinogenesis Female ionizing radiation Type 2 Receptor DNA damage DNA repair Oncology and Carcinogenesis GBM Article 03 medical and health sciences Rare Diseases Genetics medicine Animals Humans Oncology & Carcinogenesis Receptor Fibroblast Growth Factor Type 2 Cell Nucleus Lung business.industry tyrosine phosphorylation Neurosciences PTEN Phosphohydrolase Evaluation of treatments and therapeutic interventions Tyrosine phosphorylation Cell Biology medicine.disease Xenograft Model Antitumor Assays Brain Disorders Brain Cancer 030104 developmental biology Pyrimidines chemistry FGFR2 Cancer cell Cancer research biology.protein Tyrosine Rad51 Recombinase business
Zdroj:	Cancer Cell Cancer cell, vol 35, iss 3
ISSN:	1535-6108
Popis:	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 knock-in 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6c7401ad416b889b96c08547fea8cb25 https://europepmc.org/articles/PMC6946119/ Zobrazit plný text záznamu