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

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. SulmanWebster K. Cavenee, Richard D. Kolodner, Clark C. Chen, Frank B. Furnari

Neurosurgery

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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.

Original language	English (US)
Pages (from-to)	504-518.e7
Journal	Cancer Cell
Volume	35
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2019.01.020
State	Published - Mar 18 2019

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424615

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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., ... Furnari, F. B. (2019). Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair. Cancer Cell, 35(3), 504-518.e7. https://doi.org/10.1016/j.ccell.2019.01.020

Ma, J, Benitez, JA, Li, J, Miki, S, Ponte de Albuquerque, C, Galatro, T, Orellana, L, Zanca, C, Reed, R, Boyer, A, Koga, T, Varki, NM, Fenton, TR, Nagahashi Marie, SK, Lindahl, E, Gahman, TC, Shiau, AK, Zhou, H, DeGroot, J, Sulman, EP, Cavenee, WK, Kolodner, RD, Chen, CC & Furnari, FB 2019, 'Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair', Cancer Cell, vol. 35, no. 3, pp. 504-518.e7. https://doi.org/10.1016/j.ccell.2019.01.020

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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.",

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AU - Ponte de Albuquerque, Claudio

AU - Galatro, Thais

AU - Orellana, Laura

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AU - Varki, Nissi M.

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AU - Nagahashi Marie, Suely Kazue

AU - Lindahl, Erik

AU - Gahman, Timothy C.

AU - Shiau, Andrew K.

AU - Zhou, Huilin

AU - DeGroot, John

AU - Sulman, Erik P.

AU - Cavenee, Webster K.

AU - Kolodner, Richard D.

AU - Chen, Clark C.

AU - Furnari, Frank B.

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Keywords

UN SDGs

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