A STAT3-based gene signature stratifies glioma patients for targeted therapy

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A STAT3-based gene signature stratifies glioma patients for targeted therapy
Title:
A STAT3-based gene signature stratifies glioma patients for targeted therapy
Journal Title:
Nature Communications
Keywords:
Publication Date:
09 August 2019
Citation:
Tan, M.S.Y., Sandanaraj, E., Chong, Y.K. et al. A STAT3-based gene signature stratifies glioma patients for targeted therapy. Nat Commun 10, 3601 (2019). https://doi.org/10.1038/s41467-019-11614-x
Abstract:
Intratumoral heterogeneity is a hallmark of glioblastoma (GBM) tumors, thought to negatively influence therapeutic outcome. Previous studies showed that mesenchymal tumors have a worse outcome than the proneural subtype. Here we focus on STAT3 as its activation precedes the proneural-mesenchymal transition. We first establish a STAT3 gene signature that stratifies GBM patients into STAT3-high and -low cohorts. STAT3 inhibitor treatment selectively mitigates STAT3-high cell viability and tumorigenicity in orthotopic mouse xenograft models. We show the mechanism underlying resistance in STAT3-low cells by combining STAT3 signature analysis with kinome screen data on STAT3 inhibitor-treated cells. This allows us to draw connections between kinases affected by STAT3 inhibitors, their associated transcription factors and target genes. We demonstrate that dual inhibition of IGF-1R and STAT3 sensitizes STAT3-low cells and improves survival in mice. Our study underscores the importance of serially profiling tumors so as to accurately target individuals who may demonstrate molecular subtype switching.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This research was supported by the Singapore Ministry of Health’s National Medical Research Council under its Translational and Clinical Research (TCR) Flagship Programme–Tier 1 (NMRC/TCR/016-NNI/2016) and Clinician Scientist Award (NMRC/CSA-INV/0019/2017) to B.T.A. and an industry award (IRBENVOLEN01) to C.T.
Description:
ISSN:
2041-1723
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