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.
Cancer Cell. 2019 Mar 18;35(3):504-518.e7. doi: 10.1016/j.ccell.2019.01.020. Epub 2019 Feb 28.
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.
电离辐射 (IR) 和化疗是胶质母细胞瘤 (GBM) 患者的标准治疗方法，两者都会导致 DNA 损伤，但是由于治疗抵抗，临床疗效有限。我们发现了一种由 FGFR2 介导的 PTEN 酪氨酸 240 位磷酸化 (pY240-PTEN) 引起的这种抵抗的机制。pY240-PTEN 在受到 IR 治疗后迅速升高，并通过与 Ki-67 的相互作用结合到染色质上，从而促进 RAD51 的募集以促进 DNA 修复。阻断 Y240 磷酸化可使肿瘤对辐射敏感，并延长 GBM 临床前模型的存活期。Y240F-Pten 基因敲入小鼠表现出辐射敏感性。这些结果表明，FGFR 介导的 pY240-PTEN 是辐射抵抗的关键机制，是提高放射治疗效果的可行靶点。
