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Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL
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Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL
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Journal Article
Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL
2017
Overview
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.
Glioblastoma (GBM) cells are often characterized by the presence of the IDH1 R132H mutation and high expression of anti-apoptotic proteins. Here, the authors show that the inhibition of Bcl-xL is synthetically lethal in IDH1-mutated GBM models and that this effect is mediated by the oncometabolite, 2-HG, which reduces Mcl-1 protein levels.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Aniline Compounds - therapeutic use
/ Animals
/ Antineoplastic Agents - therapeutic use
/ bcl-X Protein - antagonists & inhibitors
/ Female
/ Glioma
/ Humanities and Social Sciences
/ Humans
/ Isocitrate Dehydrogenase - genetics
/ Kinases
/ Male
/ Mechanistic Target of Rapamycin Complex 1 - metabolism
/ Mutation
/ Myeloid Cell Leukemia Sequence 1 Protein - metabolism
/ Proteins
/ Science
/ Sulfonamides - therapeutic use
/ Survival
/ Tumors
