Decrypting drug actions and protein modifications by dose- and time-resolved proteomics

• 成果类型: Article
• 署名作者: Zecha, Jana; Bayer, Florian P.; Wiechmann, Svenja; Woortman, Julia; Berner, Nicola; Mueller, Julian; Schneider, Annika; Kramer, Karl; Abril-Gil, Mar; Hopf, Thomas; Reichart, Leonie; Chen, Lin; Hansen, Fynn M.; Lechner, Severin; Samaras, Patroklos; Eckert, Stephan; Lautenbacher, Ludwig; Reinecke, Maria; Hamood, Firas; Prokofeva, Polina; Vornholz, Larsen; Falcomata, Chiara; Dorsch, Madeleine; Schroeder, Ayla; Venhuizen, Anton; Wilhelm, Stephanie; Medard, Guillaume; Stoehr, Gabriele; Ruland, Juergen; Gruener, Barbara M.; Saur, Dieter; Buchner, Maike; Ruprecht, Benjamin; Hahne, Hannes; The, Matthew; Wilhelm, Mathias; Kuster, Bernhard
• 署名单位: Technical University of Munich; Helmholtz Association; German Cancer Research Center (DKFZ); Technical University of Munich; Technical University of Munich; University of Duisburg Essen; Helmholtz Association; German Cancer Research Center (DKFZ); German Center for Infection Research; Max Planck Society
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11519
• DOI: 10.1126/science.ade3925
• 发表日期: 2023-04-07
• 页码: 93-101
• 关键词: lipid raft; receptor; trastuzumab; inhibition; pertuzumab; mechanism; reveals; target; cells

摘要

Although most cancer drugs modulate the activities of cellular pathways by changing posttranslational modifications (PTMs), little is known regarding the extent and the time-and dose-response characteristics of drug-regulated PTMs. In this work, we introduce a proteomic assay called decryptM that quantifies drug-PTM modulation for thousands of PTMs in cells to shed light on target engagement and drug mechanism of action. Examples range from detecting DNA damage by chemotherapeutics, to identifying drug-specific PTM signatures of kinase inhibitors, to demonstrating that rituximab kills CD20-positive B cells by overactivating B cell receptor signaling. DecryptM profiling of 31 cancer drugs in 13 cell lines demonstrates the broad applicability of the approach. The resulting 1.8 million dose-response curves are provided as an interactive molecular resource in ProteomicsDB.