A mass spectrometry-based proteome map of drug action in lung cancer cell lines
- 1 October 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Chemical Biology
- Vol. 16 (10), 1111-+
- https://doi.org/10.1038/s41589-020-0572-3
Abstract
Mass spectrometry-based discovery proteomics is an essential tool for the proximal readout of cellular drug action. Here, we apply a robust proteomic workflow to rapidly profile the proteomes of five lung cancer cell lines in response to more than 50 drugs. Integration of millions of quantitative protein-drug associations substantially improved the mechanism of action (MoA) deconvolution of single compounds. For example, MoA specificity increased after removal of proteins that frequently responded to drugs and the aggregation of proteome changes across cell lines resolved compound effects on proteostasis. We leveraged these findings to demonstrate efficient target identification of chemical protein degraders. Aggregating drug response across cell lines also revealed that one-quarter of compounds modulated the abundance of one of their known protein targets. Finally, the proteomic data led us to discover that inhibition of mitochondrial function is an off-target mechanism of the MAP2K1/2 inhibitor PD184352 and that the ALK inhibitor ceritinib modulates autophagy.This publication has 46 references indexed in Scilit:
- ProTargetMiner as a proteome signature library of anticancer molecules for functional discoveryNature Communications, 2019
- DRUG-seq for miniaturized high-throughput transcriptome profiling in drug discoveryNature Communications, 2018
- A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug PerturbationsCell Systems, 2018
- A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 ProfilesCell, 2017
- PLATE-Seq for genome-wide regulatory network analysis of high-throughput screensNature Communications, 2017
- Expression proteomics study to determine metallodrug targets and optimal drug combinationsScientific Reports, 2017
- Reduced-representation Phosphosignatures Measured by Quantitative Targeted MS Capture Cellular States and Enable Large-scale Comparison of Drug-induced PhenotypesMolecular & Cellular Proteomics, 2016
- Functional Identification of Target by Expression Proteomics (FITExP) reveals protein targets and highlights mechanisms of action of small molecule drugsScientific Reports, 2015
- Ultrasensitive proteome analysis using paramagnetic bead technologyMolecular Systems Biology, 2014
- The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and DiseaseScience, 2006