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.
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Acknowledgements
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).
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Contributions
J.B.M. produced UT-BA07-004-ETOAC, purified didemnin B and solved its structure. M.B.P., H.S.K. and M.A.W. performed the analyses that led to the prediction that UT-BA07-004-ETOAC may inhibit AKT signaling. M.B.P., T.I.R. and Y.-H.O. performed the experiments that confirmed this prediction and elucidated the underlying mechanism. R.A.B., J.E.T. and M.B.P. designed and performed the mouse experiment. M.B.P. and T.I.R. identified cancer cell lines exhibiting exceptional sensitivity to didemnin B and determined the underlying mechanism. E.A.M. performed the elastic net analysis and the biomarker-based prediction analyses, and T.I.R. and M.B.P. tested the resulting predictions experimentally. M.D.M. provided the OCI cell lines. M.A.W. supervised the research. M.B.P. and M.A.W. wrote the manuscript.
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Supplementary information
Supplementary Text and Figures
Supplementary Results, Supplementary Figures 1–6 and full gels. (PDF 44093 kb)
Supplementary Data Set 1
Biomarker predictions and cell line information corresponding to Figure 5b. (XLSX 61 kb)
Supplementary Data Set 2
Biomarker predictions and patient sample information corresponding to Figure 5c and Supplementary Figure 5a and b. (XLSX 286 kb)
Supplementary Data Set 3
Most differentially expressed genes between didemnin B sensitive and didemnin B resistant cell lines, as determined by S2N analysis, corresponding to Figure 6a-c and Supplementary Figure 6a. (XLSX 87 kb)
Supplementary Data Set 4
Gene sets significantly enriched in didemnin B resistant vs. sensitive class. (XLSX 13 kb)
Supplementary Data Set 5
Gene sets significantly enriched in didemnin B sensitive vs. resistant class. (XLSX 11 kb)
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Potts, M., McMillan, E., Rosales, T. et al. Mode of action and pharmacogenomic biomarkers for exceptional responders to didemnin B. Nat Chem Biol 11, 401–408 (2015). https://doi.org/10.1038/nchembio.1797
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DOI: https://doi.org/10.1038/nchembio.1797
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