TERT expression is susceptible to BRAF and ETS-factor inhibition in BRAFV600E /TERT promoter double-mutated glioma

Acta Neuropathologica Communications
Lisa GablerWalter Berger

Abstract

The BRAF gene and the TERT promoter are among the most frequently altered genomic loci in low-grade (LGG) and high-grade-glioma (HGG), respectively. The coexistence of BRAF and TERT promoter aberrations characterizes a subset of aggressive glioma. Therefore, we investigated interactions between those alterations in malignant glioma. We analyzed co-occurrence of BRAFV600E and TERT promoter mutations in our clinical data (n = 8) in addition to published datasets (n = 103) and established a BRAFV600E-positive glioma cell panel (n = 9) for in vitro analyses. We investigated altered gene expression, signaling events and TERT promoter activity upon BRAF- and E-twenty-six (ETS)-factor inhibition by qRT-PCR, chromatin immunoprecipitation (ChIP), Western blots and luciferase reporter assays. TERT promoter mutations were significantly enriched in BRAFV600E-mutated HGG as compared to BRAFV600E-mutated LGG. In vitro, BRAFV600E/TERT promoter double-mutant glioma cells showed exceptional sensitivity towards BRAF-targeting agents. Remarkably, BRAF-inhibition attenuated TERT expression and TERT promoter activity exclusively in double-mutant models, while TERT expression was undetectable in BRAFV600E-only cells. Various ETS-factors were broadly...Continue Reading

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Citations

Aug 1, 2020·Oncogene·Adam N Guterres, Jessie Villanueva
Apr 12, 2020·Molecular Cancer Research : MCR·Josh Lewis SternFranklin W Huang
Apr 23, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Christine PirkerWalter Berger
Feb 7, 2021·Journal of Cancer Research and Clinical Oncology·Branka PowterTherese M Becker
Jul 28, 2021·International Journal of Cancer. Journal International Du Cancer·Sivaramakrishna RachakondaRajiv Kumar

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Methods Mentioned

BETA
FCS
scraping
Protein Assay
electrophoresis
PCR
transfection
Assay

Clinical Trials Mentioned

NCT01677741
NCT01748149
NCT03363217
NCT01089101
NCT02285439
NCT03213691
NCT02684058
NCT03340506
NCT02034110

Software Mentioned

Ion Torrent PGM System
ImageJ
COSMIC
CFX Connect Real - Time PCR Detection System
GraphPad Prism
Ion Torrent Suite Software
DESeq2
Ion AmpliSeq Cancer Hotspot Panel

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