University of Pennsylvania School of Medicine Department of Radiology

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University of Pennsylvania School of Medicine Department of Radiology Metabolic flux analysis of mantle cell lymphoma cells upon Bruton tyrosine kinase inhibition Seung-Cheol Lee, PhD University of Pennsylvania School of Medicine Department of Radiology

13C Metabolic Flux Analysis (MFA) Chance (1984) – heart, NMR Malloy (1988) – heart, NMR Mason, Gruetter, Rothman (1995) – brain, NMR Wiechert (1997) – microorganism, NMR, MS Stephanopoulos (2009) – cancer cells, MS Shestov (2016) – cancer cells, NMR

Melanoma cells, Dynamic MFA Shestov, Mancuso and Lee et al., Journal of Biological Chemistry 2016

Application of MFA to lymphoma cells and BTK inhibitor Bruton tyrosine kinase (BTK) inhibitor Mantle cell lymphoma (MCL) Cytostatic drug Find which pathways are affected by the inhibitor and determine metabolic pathways to be further targeted

Differential response of MCL cells to BTK inhibitor Jeko RL

1H NMR 48 hr treatment with 500 nM ibrutnib p=0.0003 p=0.01 p=0.003

Metabolite 13C enrichment determination (Proton Observe Carbon Edited NMR) 2.4 2.2 2.0 1.8 1.6 1.4 1.2 PPM 2.6 12C Glu 12C Ala 12C Lac 13C Glu 13C Ala 13C Lac RL cells Jeko cells p=0.01 p=0.02 48 hr treatment + incubation with [1,6]glucose for 8 hr

Glutamate mulitiplet ratio determination 13C NMR 34.8 34.6 34.4 34.2 34.0 33.8 PPM 4s 4d34 28.2 28.0 27.8 27.6 3s 3d43 Glu4 Glu3 RL cells Jeko cells p=0.03

Mass balance equations Chemical mass balance 13C isotope balance

Metabolic network

Determined metabolic fluxes

Correlation with RNA-seq analysis * data not shown due to very low gene expression of this LDH isoform in JeKo-1 cells

Treatment of MCL cells with a glutaminase inhibitor Cell growth (MTT assay)

Summary We have determined various metabolic fluxes of MCL cells (RL and Jeko) upon perturbation with BTK inhibition by using 13C NMR metabolic flux analysis. Glutaminolytic pathway was found to be unaffected by BTK inhibition in Jeko cells . Treatment of Jeko cells with a glutaminase inhibitor resulted in profound growth inhibition.

Acknowledgement NIH R01-CA172820 R01-CA129544