Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL

Georg Karpel-Massler,Takashi Tsujiuchi,Peter Canoll,Chiaki Tsuge Ishida,Jeffrey N Bruce,Franklin Garcia,Yiru Zhang,Chang Shu,Elena Bianchetti,Kevin A Roth,Markus D Siegelin,Matei A Banu

doi:10.1038/s41467-017-00984-9

Georg Karpel-Massler, Takashi Tsujiuchi + Show 10 more

Open Access

https://doi.org/10.1038/s41467-017-00984-9

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Abstract

Certain gliomas often harbor a mutation in the activity center of IDH1 (R132H), which leads to the production of the oncometabolite 2-R-2-hydroxyglutarate (2-HG). In six model systems, including patient-derived stem cell-like glioblastoma cultures, inhibition of Bcl-xL induces significantly more apoptosis in IDH1-mutated cells than in wild-type IDH1 cells. Anaplastic astrocytoma samples with mutated IDH1 display lower levels of Mcl-1 than IDH1 wild-type tumors and specific knockdown of Mcl-1 broadly sensitizes glioblastoma cells to Bcl-xL inhibition-mediated apoptosis. Addition of 2-HG to glioblastoma cultures recapitulates the effects of the IDH mutation on intrinsic apoptosis, shuts down oxidative phosphorylation and reduces ATP levels in glioblastoma cells. 2-HG-mediated energy depletion activates AMPK (Threonine 172), blunting protein synthesis and mTOR signaling, culminating in a decline of Mcl-1. In an orthotopic glioblastoma xenograft model expressing mutated IDH1, Bcl-xL inhibition leads to long-term survival. These results demonstrate that IDH1-mutated gliomas are particularly vulnerable to Bcl-xL inhibition.

Highlights

Certain gliomas often harbor a mutation in the activity center of IDH1 (R132H), which leads to the production of the oncometabolite 2-R-2-hydroxyglutarate (2-HG)
Transduced U87MG and T98G glioblastoma cells, bearing the wild-type or mutated form of IDH1 were treated with increasing concentrations of the BH-3 mimetic ABT263, a known inhibitor of both Bcl-xL and Bcl-2
To gain further insight on how general this biological observation is we extended our studies to an isogenic model using HCT116 (IDH1-WT/IDH1-R132H) colorectal cancer cells and two patient-derived IDH1-R132H expressing glioma stem-like cells, NCH612 and BT-142

Summary

Introduction

Certain gliomas often harbor a mutation in the activity center of IDH1 (R132H), which leads to the production of the oncometabolite 2-R-2-hydroxyglutarate (2-HG). In six model systems, including patient-derived stem cell-like glioblastoma cultures, inhibition of Bcl-xL induces significantly more apoptosis in IDH1-mutated cells than in wild-type IDH1 cells. Anaplastic astrocytoma samples with mutated IDH1 display lower levels of Mcl-1 than IDH1 wild-type tumors and specific knockdown of Mcl-1 broadly sensitizes glioblastoma cells to Bcl-xL inhibition-mediated apoptosis. In an orthotopic glioblastoma xenograft model expressing mutated IDH1, Bcl-xL inhibition leads to long-term survival. These results demonstrate that IDH1-mutated gliomas are vulnerable to Bcl-xL inhibition. We demonstrate that inhibition of Bcl-xL causes synthetic lethality in IDH1-mutated glioblastoma cells in vitro and in vivo and that these effects are mediated by the oncometabolite, 2-HG, which reduces Mcl-1 protein levels. Our findings reveal that IDH1-mutated gliomas display lower protein levels of Mcl-1

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