@article{2a7ab4fc316c4882b0d29c69a1f39244,
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.",
author = "Potts, {Malia B.} and McMillan, {Elizabeth A.} and Rosales, {Tracy I.} and Kim, {Hyun Seok} and Ou, {Yi Hung} and Toombs, {Jason E.} and Brekken, {Rolf A.} and Minden, {Mark D.} and MacMillan, {John B.} and White, {Michael A.}",
note = "Funding Information: We thank T. Molinski for providing additional Trididemnum solidum material; D. Sabatini and N. Gray for the Torin1; J. Willson and S. Markowitz for the Vaco colon cancer cell lines; K. Huffman, M. Peyton, A. Gazdar and J. Minna for the lung and breast cancer cell lines; J. Shay for the human colonic epithelial cells; X. Wang for the U2OS GFP-LC3 cells; J. Brugarolas for the REDD1-knockout MEFs; F. Grinnell for the BR5 fibroblasts; R. Potts for the U2OS cells and J. Mendell for the P493 cells. We also thank N. Williams for formulating didemnin B for animal delivery. This study was supported by the Welch Foundation (I-1414, I-1689), the US National Cancer Institute (CA071443, CA176284, CA149833) and the Cancer Prevention and Research Institute of Texas (RP120718, RP110708). M.B.P. was supported by a Komen for the Cure Postdoctoral Fellowship. E.A.M. was supported in part by the US National Institutes of Health (2T32GM008203). Y.-H.O. and H.S.K. were supported by fellowships from the Cancer Interventions and Discoveries Program (RP101496). Publisher Copyright: {\textcopyright} 2015 Nature Chemical Biology.",
year = "2015",
month = jun,
day = "1",
doi = "10.1038/nchembio.1797",
language = "English (US)",
volume = "11",
pages = "401--408",
journal = "Nature chemical biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "6",
}