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NPJ Syst Biol Appl. 2018 Jul 2;4:26. doi: 10.1038/s41540-018-0064-1. eCollection 2018.

Systems pharmacology using mass spectrometry identifies critical response nodes in prostate cancer.

Author information

1
1Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Auguste Piccard Hof 1, Zürich, Switzerland.
2
2Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
3
3Computational Biology Center, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY USA.
4
4Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Graduate School of Medical Sciences, 1300 York Ave., New York, NY USA.
5
5Department of Pharmacology, Yale University School of Medicine, West Haven, CT USA.
6
6cBio Center, Dana-Farber Cancer Institute, Boston, MA USA.
7
7Department of Cell Biology, Harvard Medical School, Boston, MA USA.
8
8Faculty of Science, University of Zürich, Zürich, Switzerland.
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Contributed equally

Abstract

In the United States alone one in five newly diagnosed cancers in men are prostate carcinomas (PCa). Androgen receptor (AR) status and the PI3K-AKT-mTOR signal transduction pathway are critical in PCa. After initial response to single drugs targeting these pathways resistance often emerges, indicating the need for combination therapy. Here, we address the question of efficacy of drug combinations and development of resistance mechanisms to targeted therapy by a systems pharmacology approach. We combine targeted perturbation with detailed observation of the molecular response by mass spectrometry. We hypothesize that the molecular short-term (24 h) response reveals details of how PCa cells adapt to counter the anti-proliferative drug effect. With focus on six drugs currently used in PCa treatment or targeting the PI3K-AKT-mTOR signal transduction pathway, we perturbed the LNCaP clone FGC cell line by a total of 21 treatment conditions using single and paired drug combinations. The molecular response was analyzed by the mass spectrometric quantification of 52 proteins. Analysis of the data revealed a pattern of strong responders, i.e., proteins that were consistently downregulated or upregulated across many of the perturbation conditions. The downregulated proteins, HN1, PAK1, and SPAG5, are potential early indicators of drug efficacy and point to previously less well-characterized response pathways in PCa cells. Some of the upregulated proteins such as 14-3-3 proteins and KLK2 may be useful early markers of adaptive response and indicate potential resistance pathways targetable as part of combination therapy to overcome drug resistance. The potential of 14-3-3ζ (YWHAZ) as a target is underscored by the independent observation, based on cancer genomics of surgical specimens, that its DNA copy number and transcript levels tend to increase with PCa disease progression. The combination of systematic drug perturbation combined with detailed observation of short-term molecular response using mass spectrometry is a potentially powerful tool to discover response markers and anti-resistance targets.

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