In:
Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii270-vii270
Abstract:
Glioblastoma (GBM) remains an incurable disease, requiring more effective therapies. Through CRISPR and RNAi library screening interrogation we identified several TCA-cycle enzymes as essential for GBM growth. By combining a transcriptome and metabolite screening analyses we discovered that inhibition of the TCA-cycle by the clinically validated drug compound, CPI-613, is synthetically lethal with Bcl-xL loss of function (genetically and through the clinically validated BH3-mimetic, ABT263) in patient-derived xenograft as well neurosphere GBM cultures. Carbon tracing experiments (U-13 C-glucose and U-13 C-glutamine) and extracellular flux analysis showed that CPI-613 interferes with mitochondrial respiration. In turn, CPI-613 mediated energy deprivation drives 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 rescued from cell death induced by CPI-613 as well as by the combination treatment of ABT263 and CPI-613 in model systems of GBM. In patient-derived xenograft models of GBM in mice, the combination treatment of ABT263 and CPI613 suppressed tumor growth more potently than each compound on its own. Therefore, combined inhibition of Bcl-xL along with interference of the TCA-cycle might be a novel treatment strategy for GBM.
Type of Medium:
Online Resource
ISSN:
1522-8517
,
1523-5866
DOI:
10.1093/neuonc/noac209.1044
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2022
detail.hit.zdb_id:
2094060-9
