title: Mode of action and pharmacogenomic biomarkers for exceptional responders to didemnin B.
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.
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Malia B
authors: MB
authors: Potts
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Elizabeth A
authors: EA
authors: McMillan
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Tracy I
authors: TI
authors: Rosales
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Hyun Seok
authors: HS
authors: Kim
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Yi-Hung
authors: YH
authors: Ou
authors: Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Jason E
authors: JE
authors: Toombs
authors: Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Rolf A
authors: RA
authors: Brekken
authors: 1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [2] Ontario Cancer Institute and Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
authors: Mark D
authors: MD
authors: Minden
authors: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: John B
authors: JB
authors: MacMillan
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Michael A
authors: MA
authors: White
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology*; D055106:Genome-Wide Association Study; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D020648:Peptide Elongation Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D010597:Pharmacogenetics; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013869:Thiolester Hydrolases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; C469991:DDIT4 protein, human; D047630:Depsipeptides; C094814:EEF1A1 protein, human; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D020648:Peptide Elongation Factor 1; D014157:Transcription Factors; C030051:didemnins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D013869:Thiolester Hydrolases; C416054:PPT1 protein, human