TMET-38 - Loss of function of CDK7 is synthetically lethal with fatty acid oxidation inhibition 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
CS

Chang Shu, n/a

Columbia University
New York, United States
HA

Hasan Akman, PhD

Columbia University
New York, United States
BI

Benjamin Izar

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
JB

Jeffrey Bruce

Columbia University
New York, United States
PC

Peter D. Canoll, MD, PhD

Columbia University
New York, United States
Markus D. Siegelin, MD, PhD

Columbia University
New York, United States

CDK7 has been identified as a potential drug target for glioblastoma (GBM), a highly lethal primary brain tumor. However, resistance to therapy develops quickly, which may be facilitated by drug-induced reprogramming of metabolism. By combination of a transcriptome and metabolite screening analyses followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis we demonstrated that both genetic and pharmacological (YKL-5-124 and THZ1) CDK7 inhibition elicited substantial metabolic reprogramming. Specifically, CDK7i elicited an increase of oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO) manifested by enhanced labeling of citric acid cycle intermediates from palmitic acid. Consistently, the combination treatment of CDK7i inhibitors with blockers of FAO (etomoxir) or cellular respiration (gamitrinib) exerted substantial synergistic growth inhibition in patient derived xenograft as well as neurosphere GBM cultures, which was mainly driven by a collapse of oxidative energy metabolism. In turn, exogenous administration of adenosine triphosphate partially rescued from the cell death induced by the combination treatment. Moreover, the combination treatment activated intrinsic apoptosis through a reduction of both Mcl-1 and Bcl-xL as demonstrated by rescue experiments. Finally, the combined administration of YKL-5-124 and etomoxir extended overall in an orthotopic patient-derived xenograft model of GBM. In summary, these data support that simultaneous targeting of CDK7 and FAO might be a potential novel therapy against GBM.