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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.

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