Induction of synthetic lethality in IDH1 mutated gliomas through inhibition of Bcl xL
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.
Nature Communications