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.
Highlights
Intratumoral heterogeneity is a hallmark of glioblastoma (GBM) tumors, thought to negatively influence therapeutic outcome
Contingency analyses accounting for The Cancer Genome Atlas (TCGA) GI molecular subtypes and the World Health Organization (WHO) classification scheme including molecular and clinical indicators, demonstrate that STAT3-high defines a patient cohort enriched in the mesenchymal and classical
The utility of STAT3 inhibitors has largely been confined to myeloproliferative disorders, in part due to their poor blood–brain barrier (BBB) penetration
Summary
Intratumoral heterogeneity is a hallmark of glioblastoma (GBM) tumors, thought to negatively influence therapeutic outcome. 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. The revised World Health Organization (WHO) classification scheme for brain tumors incorporates these molecular markers to influence treatment decision[1]. These efforts highlight the necessity to prescribe treatment regimens based on a stratified population. We focused on signal transducers and activators of transcription (STAT3) where its activation has been demonstrated to effect a transition in molecular subtype to the aggressive mesenchymal profile[6]. The genes encoding JAK enzymes, JAK2, frequently contain gain-of-function mutations[12]
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