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

Malia B. Potts, Elizabeth A. McMillan, Tracy I. Rosales, Hyun Seok Kim, Yi Hung Ou, Jason E. Toombs, Rolf A. Brekken, Mark D. Minden, John B. MacMillan, Michael A. White

Research output: Contribution to journalArticle

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)401-408
Number of pages8
JournalNature Chemical Biology
Volume11
Issue number6
DOIs
StatePublished - Jun 1 2015

    Fingerprint

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this