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
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.
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.