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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Liberti, MV; Dai, Z; Wardell, SE; Baccile, JA; Liu, X; Gao, X; Baldi, R; Mehrmohamadi, M; Johnson, MO; Madhukar, NS; Shestov, AA; Chio, IIC; Elemento, O; Rathmell, JC; Schroeder, FC; McDonnell, DP; Locasale, JW

Published Date

  • October 3, 2017

Published In

Volume / Issue

  • 26 / 4

Start / End Page

  • 648 - 659.e8

PubMed ID

  • 28918937

Pubmed Central ID

  • 28918937

Electronic International Standard Serial Number (EISSN)

  • 1932-7420

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2017.08.017

Language

  • eng

Conference Location

  • United States