A Predictive Model for Selective Targeting of the Warburg Effect through GAPDH Inhibition with a Natural Product

Liberti, M. V., Dai, Z., Wardell, S. E., Baccile, J. A., Liu, X., Gao, X., Baldi, R., Mehrmohamadi, M., Johnson, M. O., Madhukar, N. S., Shestov, A. A., Chio, I. I. C., Elemento, O., Rathmell, J. C., Schroeder, F. C., McDonnell, D. P., Locasale, J. W. (2017) A Predictive Model for Selective Targeting of the Warburg Effect through GAPDH Inhibition with a Natural Product. Cell Metab, 26 (4). pp. 648-659. ISSN 1550-4131

URL: https://www.ncbi.nlm.nih.gov/pubmed/28918937
DOI: 10.1016/j.cmet.2017.08.017

Abstract

Targeted cancer therapies that use genetics are successful, but principles for selectively targeting tumor metabolism that is also dependent on the environment remain unknown. We now show that differences in rate-controlling enzymes during the Warburg effect (WE), the most prominent hallmark of cancer cell metabolism, can be used to predict a response to targeting glucose metabolism. We establish a natural product, koningic acid (KA), to be a selective inhibitor of GAPDH, an enzyme we characterize to have differential control properties over metabolism during the WE. With machine learning and integrated pharmacogenomics and metabolomics, we demonstrate that KA efficacy is not determined by the status of individual genes, but by the quantitative extent of the WE, leading to a therapeutic window in vivo. Thus, the basis of targeting the WE can be encoded by molecular principles that extend beyond the status of individual genes.

Item Type: Paper
Uncontrolled Keywords: Warburg effect cancer metabolism glucose metabolism metabolic control analysis metabolic flux analysis metabolomics natural product pharmacogenomics precision medicine systems biology
Subjects: diseases & disorders > cancer
organs, tissues, organelles, cell types and functions > organs types and functions > metabolism
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date Deposited: 21 Sep 2017 20:19
Last Modified: 25 Oct 2017 16:39
PMCID: PMC5629112
Related URLs:
URI: http://repository.cshl.edu/id/eprint/35286

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