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A STAT3-based gene signature stratifies glioma patients for targeted therapy
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Journal Article
A STAT3-based gene signature stratifies glioma patients for targeted therapy
2019
Overview
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.
STAT3 activates distinct transcriptional programmes within cancer cells. In this study, the authors find that, in glioma, a STAT3-mediated expression signature can stratify patients for targeted precision therapy.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 38/39
/ 38/77
/ 64/60
/ 82/51
/ 82/80
/ 96/106
/ 96/44
/ Animals
/ Dose-Response Relationship, Drug
/ Gene Expression Regulation, Neoplastic - genetics
/ Genetic Predisposition to Disease - genetics
/ Glioma
/ Humanities and Social Sciences
/ Humans
/ Insulin-Like Growth Factor Binding Protein 2 - genetics
/ Insulin-Like Growth Factor Binding Protein 2 - metabolism
/ Kinases
/ Mice
/ Receptor, IGF Type 1 - antagonists & inhibitors
/ Receptor, IGF Type 1 - genetics
/ Science
/ STAT3 Transcription Factor - antagonists & inhibitors
/ STAT3 Transcription Factor - genetics
/ STAT3 Transcription Factor - metabolism
/ Tumors
