Mode of action and pharmacogenomic biomarkers for exceptional responders to didemnin B

Nat Chem Biol. 2015 Jun;11(6):401-8. doi: 10.1038/nchembio.1797. Epub 2015 Apr 13.

Abstract

Modern cancer treatment employs many effective chemotherapeutic agents originally discovered from natural sources. The cyclic depsipeptide didemnin B has demonstrated impressive anticancer activity in preclinical models. Clinical use has been approved but is limited by sparse patient responses combined with toxicity risk and an unclear mechanism of action. From a broad-scale effort to match antineoplastic natural products to their cellular activities, we found that didemnin B selectively induces rapid and wholesale apoptosis through dual inhibition of PPT1 and EEF1A1. Furthermore, empirical discovery of a small panel of exceptional responders to didemnin B allowed the generation of a regularized regression model to extract a sparse-feature genetic biomarker capable of predicting sensitivity to didemnin B. This may facilitate patient selection in a fashion that could enhance and expand the therapeutic application of didemnin B against neoplastic disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Biomarkers / metabolism
  • Cell Line, Tumor
  • Depsipeptides / pharmacology*
  • Genome-Wide Association Study
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / genetics
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Peptide Elongation Factor 1 / antagonists & inhibitors*
  • Peptide Elongation Factor 1 / genetics
  • Pharmacogenetics*
  • Protein Biosynthesis / drug effects
  • Protein Biosynthesis / genetics
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Thiolester Hydrolases
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics

Substances

  • Antineoplastic Agents
  • Biomarkers
  • DDIT4 protein, human
  • Depsipeptides
  • EEF1A1 protein, human
  • Membrane Proteins
  • Multiprotein Complexes
  • Peptide Elongation Factor 1
  • Transcription Factors
  • didemnins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Thiolester Hydrolases
  • PPT1 protein, human