TMET-39 - Inhibition of the TCA-cycle is synthetically lethal with loss of function of Bcl-xL in glioblastoma

Friday, November 18, 2022

7:30 PM – 9:30 PM ET

Location: West/Central Hall

Poster Presenter(s)

Trang Nguyen, PhD (she/her/hers)

Columbia University
New York, United States

Author(s)

ES

Enyuan Shang, PhD

Bronx Community College
New York, United States
CT

Consuelo Torrini

Massachusetts General Hospital
Boston, United States
CS

Chang Shu, n/a

Columbia University
New York, United States
MW

Mike-Andrew Westhoff, PhD

Ulm University Medical Center
Ulm, Germany
GK

Georg Karpel-Massler, MD PhD

Ulm University Medical Center
Ulm, Germany
Markus D. Siegelin, MD, PhD

Columbia University
New York, United States

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.