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OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.
JCI Insight 2024 March 15
Glioblastoma (GBM) remains an incurable disease, requiring more effective therapies. Through interrogation of publicly available CRISPR and RNAi library screens, we identified the alpha-ketoglutarate dehydrogenase (OGDH) gene, which encodes for an enzyme that is part of the tricarboxylic acid cycle (TCA cycle) as essential for GBM growth. Moreover, by combining a transcriptome and metabolite screening analyses we discovered that loss of function of OGDH by the clinically validated drug compound, CPI-613, was synthetically lethal with Bcl-xL inhibition (genetically and through the clinically validated BH3-mimetic, ABT263) in patient-derived xenograft as well neurosphere GBM cultures. CPI-613 mediated energy deprivation drove an integrated stress response with an up-regulation of the BH3-only domain protein, Noxa in an ATF4 dependent manner as demonstrated by genetic loss of function experiments. Consistently, silencing of Noxa attenuated cell death induced by CPI-613 in model systems of GBM. In patient-derived xenograft models of GBM in mice, the combination treatment of ABT263 and CPI-613 suppressed tumor growth and extended animal survival more potently than each compound on its own. Therefore, combined inhibition of Bcl-xL along with interference of the TCA-cycle might be a treatment strategy for GBM.
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