A mass spectrometry-based proteome map of drug action in lung cancer cell lines.

Nature Chemical Biology
Benjamin RuprechtAn Chi

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.

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Citations

Dec 9, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Quentin T L PasquerSascha Hoogendoorn
Feb 12, 2021·Expert Review of Proteomics·Vivian Weiwen XueWilliam Chi Cho
Apr 21, 2021·Expert Review of Proteomics·Olson Tsang, Jason W H Wong
Jun 8, 2021·Molecular Therapy Oncolytics·Xiao-Li YangDa Fu
Jul 30, 2021·Expert Review of Proteomics·Jennie R LillMarkus Schirle
Dec 12, 2020·ACS Chemical Biology·Nancy WiebelhausMichael C Fitzgerald

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Methods Mentioned

BETA
proteome
proteomic profiling
fluorescence microscopy
pulldowns
PCR
pulldown
acetylation
PCA

Software Mentioned

Acapella
Andromeda
Treemap
String
Harmony controller
iLINCS
Cytoscape
Perseus
BZ
GraphPad Prism

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