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

Melanie Si Yan Tan; Edwin Sandanaraj; Yuk Kien Chong; See Wee Lim; Lynnette Wei Hsien Koh; Wai Hoe Ng; Nguan Soon Tan; Patrick Tan; Beng Ti Ang; Carol Tang

doi:10.1038/s41467-019-11614-x

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

Nat Commun. 2019 Aug 9;10(1):3601. doi: 10.1038/s41467-019-11614-x.

Authors

Melanie Si Yan Tan^{1

2}, Edwin Sandanaraj^{1

2

3}, Yuk Kien Chong¹, See Wee Lim¹, Lynnette Wei Hsien Koh^{1

2}, Wai Hoe Ng^{4

5}, Nguan Soon Tan^{2

6

7}, Patrick Tan^{5

8}, Beng Ti Ang^{9

10

11

12}, Carol Tang^{13

14

15}

Affiliations

¹ Neuro-Oncology Research Laboratory, Department of Research, National Neuroscience Institute, Singapore, Singapore.
² School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
³ Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
⁴ Department of Neurosurgery, National Neuroscience Institute, Singapore, Singapore.
⁵ Duke-National University of Singapore Medical School, Singapore, Singapore.
⁶ Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
⁷ Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore, Singapore.
⁸ Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
⁹ Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. [email protected].
¹⁰ Department of Neurosurgery, National Neuroscience Institute, Singapore, Singapore. [email protected].
¹¹ Duke-National University of Singapore Medical School, Singapore, Singapore. [email protected].
¹² Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. [email protected].
¹³ Neuro-Oncology Research Laboratory, Department of Research, National Neuroscience Institute, Singapore, Singapore. [email protected].
¹⁴ Duke-National University of Singapore Medical School, Singapore, Singapore. [email protected].
¹⁵ Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, Singapore. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Survival
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Synergism
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / genetics
Gene Knockdown Techniques
Genetic Predisposition to Disease / genetics*
Glioblastoma / drug therapy*
Glioblastoma / genetics*
Humans
Imidazoles / pharmacology
Insulin-Like Growth Factor Binding Protein 2 / genetics
Insulin-Like Growth Factor Binding Protein 2 / metabolism
Mice
Pyrazines / pharmacology
Pyrazoles / pharmacology
Pyrimidines / pharmacology
Receptor, IGF Type 1 / antagonists & inhibitors
Receptor, IGF Type 1 / genetics
STAT3 Transcription Factor / antagonists & inhibitors
STAT3 Transcription Factor / genetics*
STAT3 Transcription Factor / metabolism*
Temozolomide / pharmacology
Xenograft Model Antitumor Assays

Substances

3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
AZD 1480
Imidazoles
Insulin-Like Growth Factor Binding Protein 2
Pyrazines
Pyrazoles
Pyrimidines
STAT3 Transcription Factor
Receptor, IGF Type 1
Temozolomide