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Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair
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- Ma, Jianhui (author)
- Univ Calif San Diego, Ludwig Inst Canc Res, San Diego Branch, 9500 Gilman Dr, La Jolla, CA 92093 USA. i, Jie; Cavenee, Webster K.; Kolodner, Richard D.; Chen, Clark C.; Furnari, Frank B.
- Benite, Jorge A. (author)
- Li, Jie (author)
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- Miki, Shunichiro (author)
- de Albuquerqu, Claudio Ponte (author)
- Galatro, Thais (author)
- Zanca, Ciro (author)
- Reed, Rachel (author)
- Boyer, Antonia (author)
- Koga, Tomoyuki (author)
- Varki, Nissi M. (author)
- Fenton, Tim R. (author)
- Marie, Suely Kazue Nagahashi (author)
- Gahman, Timothy C. (author)
- Shiau, Andrew K. (author)
- Zhou, Huilin (author)
- DeGroot, John (author)
- Sulman, Erik P. (author)
- Cavenee, Webster K. (author)
- Kolodner, Richard D. (author)
- Chen, Clark C. (author)
- Furnari, Frank B. (author)
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- Univ Calif San Diego, Ludwig Inst Canc Res, San Diego Branch, 9500 Gilman Dr, La Jolla, CA 92093 USA i, Jie; Cavenee, Webster K.; Kolodner, Richard D.; Chen, Clark C.; Furnari, Frank B. Institutionen för biokemi och biofysik (creator_code:org_t)
- Elsevier BV, 2019
- 2019
- English.
- In: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 35:3, s. 504-518.e7
- Journal article (peer-reviewed)
Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
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