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Sci. Signal., 9 July 2013
Vol. 6, Issue 283, p. ra55
[DOI: 10.1126/scisignal.2003900]


Blockade of Glioma Proliferation Through Allosteric Inhibition of JAK2

Kunyan He1*, Qi Qi1*, Chi-Bun Chan1, Ge Xiao2, Xia Liu1, Carol Tucker-Burden1, Liya Wang3, Hui Mao3, Xiang Lu4, Frank E. McDonald4, Hongbo Luo5, Qi-Wen Fan6, William A. Weiss6, Shi-Yong Sun7, Daniel J. Brat1, and Keqiang Ye1{dagger}

1 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
2 Centers for Disease Control and Prevention, 4770 Buford Highway, Atlanta, GA 30341, USA.
3 Department of Radiology, Center for Systems Imaging, Emory University, Atlanta, GA 30322, USA.
4 Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
5 Department of Pathology and Lab Medicine, Harvard Medical School and Children’s Hospital Boston, 10214 Karp Research Building, 1 Blackfan Circle, Boston, MA 02115, USA.
6 Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
7 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.

* These authors contributed equally to this work.

Abstract: The gene that encodes the epidermal growth factor receptor (EGFR) is frequently overexpressed or mutated in human cancers, including glioblastoma. However, the efficacy of EGFR-targeted small-molecule inhibitors or monoclonal antibodies in glioblastomas that also have mutation or deletion of the gene encoding phosphatase and tensin homolog (PTEN) has been modest. We found that EGFR signaling was blocked by a small molecule (G5-7) that selectively inhibited Janus kinase 2 (JAK2)–mediated phosphorylation and activation of EGFR and STAT3 (signal transducer and activator of transcription 3) by binding to JAK2, thereby decreasing the activity of downstream signaling by mTOR (mammalian target of rapamycin) and inducing cell cycle arrest. G5-7 inhibited the proliferation of PTEN-deficient glioblastoma cell lines harboring a constitutively active variant of EGFR (U87MG/EGFRvIII) and human glioblastoma explant neurosphere cultures, but the drug only weakly inhibited the proliferation of either glioblastoma cell lines that were wild type for EGFR and stably transfected with PTEN (U87MG/PTEN) or normal neural progenitor cells and astrocytes. Additionally, G5-7 reduced vascular endothelial growth factor (VEGF) secretion and endothelial cell migration and induced apoptosis in glioblastoma xenografts, thereby suppressing glioblastoma growth in vivo. Furthermore, G5-7 was more potent than EGFR or JAK2 inhibitors that interfere with either ligand or adenosine 5'-triphosphate (ATP) binding at impeding glioblastoma cell proliferation, demonstrating that this allosteric JAK2 inhibitor may be an effective clinical strategy.

{dagger}Corresponding author. E-mail: kye{at}

Citation: K. He, Q. Qi, C.-B. Chan, G. Xiao, X. Liu, C. Tucker-Burden, L. Wang, H. Mao, X. Lu, F. E. McDonald, H. Luo, Q.-W. Fan, W. A. Weiss, S.-Y. Sun, D. J. Brat, K. Ye, Blockade of Glioma Proliferation Through Allosteric Inhibition of JAK2. Sci. Signal. 6, ra55 (2013).

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Science Signaling Podcast: 9 July 2013.
K. Ye and A. M. VanHook (2013)
Science Signaling 6, pc17
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