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

Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Yiru Zhang, Chang Shu, Takashi Tsujiuchi, Matei A. Banu, Franklin Garcia, Kevin A. Roth, Jeffrey N. Bruce, Peter Canoll and Markus D. Siegelin ()
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Georg Karpel-Massler: Columbia University Medical Center
Chiaki Tsuge Ishida: Columbia University Medical Center
Elena Bianchetti: Columbia University Medical Center
Yiru Zhang: Columbia University Medical Center
Chang Shu: Columbia University Medical Center
Takashi Tsujiuchi: Columbia University Medical Center
Matei A. Banu: Columbia University Medical Center
Franklin Garcia: Columbia University Medical Center
Kevin A. Roth: Columbia University Medical Center
Jeffrey N. Bruce: Columbia University Medical Center
Peter Canoll: Columbia University Medical Center
Markus D. Siegelin: Columbia University Medical Center

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00984-9

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