%0 Journal Article %1 KarpelMassler:2017:Nat-Commun:29057925 %A Karpel-Massler, G %A Ishida, C T %A Bianchetti, E %A Zhang, Y %A Shu, C %A Tsujiuchi, T %A Banu, M A %A Garcia, F %A Roth, K A %A Bruce, J N %A Canoll, P %A Siegelin, M D %D 2017 %J Nat Commun %K IDH1 MUSTREAD cancer-research fulltext glioma %N 1 %P 1067-1067 %R 10.1038/s41467-017-00984-9 %T Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL %U https://www.ncbi.nlm.nih.gov/pubmed/29057925 %V 8 %X 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.

@article{KarpelMassler:2017:Nat-Commun:29057925, 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.}, added-at = {2017-12-26T19:35:19.000+0100}, author = {Karpel-Massler, G and Ishida, C T and Bianchetti, E and Zhang, Y and Shu, C and Tsujiuchi, T and Banu, M A and Garcia, F and Roth, K A and Bruce, J N and Canoll, P and Siegelin, M D}, biburl = {https://www.bibsonomy.org/bibtex/299a1c94dcc2836088fe125a508403dec/marcsaric}, description = {Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL. - PubMed - NCBI}, doi = {10.1038/s41467-017-00984-9}, interhash = {02bdd8e47120032ec825406d7c6374d7}, intrahash = {99a1c94dcc2836088fe125a508403dec}, journal = {Nat Commun}, keywords = {IDH1 MUSTREAD cancer-research fulltext glioma}, month = oct, number = 1, pages = {1067-1067}, pmid = {29057925}, timestamp = {2017-12-26T19:35:19.000+0100}, title = {Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL}, url = {https://www.ncbi.nlm.nih.gov/pubmed/29057925}, volume = 8, year = 2017 }