A mass spectrometry-based proteome map of drug action in lung cancer cell lines.
Benjamin RuprechtJulie Di BernardoZhao WangXuan MoOleg UrsuMatthew ChristopherRafael B FernandezLi ZhengBrian D DillHuijun WangYuting XuAndy LiawJonathan D MortisonNirodhini SiriwardanaBrian AndresenMeir GlickJames R TataVictoria KutilekIvan Cornella-TaracidoAn ChiPublished in: Nature chemical biology (2020)
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.
Keyphrases
- mass spectrometry
- liquid chromatography
- high resolution
- protein protein
- drug induced
- electronic health record
- adverse drug
- cell death
- binding protein
- small molecule
- amino acid
- label free
- emergency department
- high performance liquid chromatography
- gas chromatography
- high throughput
- endoplasmic reticulum stress
- high density
- ms ms
- big data
- wastewater treatment
- tandem mass spectrometry
- endoplasmic reticulum
- bioinformatics analysis