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

Authors
 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 
Citation
 NATURE CHEMICAL BIOLOGY, Vol.11(6) : 401-408, 2015 
Journal Title
NATURE CHEMICAL BIOLOGY
ISSN
 1552-4450 
Issue Date
2015
MeSH
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 ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/genetics
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.
Files in This Item:
T201501449.pdf Download
DOI
10.1038/nchembio.1797
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Hyun Seok(김현석) ORCID logo https://orcid.org/0000-0003-4498-8690
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/140137
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