Decrypting drug actions and protein modifications by dose- and time-resolved proteomics
Jana Zecha, Florian Bayer, Svenja Wiechmann, Julia Rechenberger, Nicola Berner, Julian Müller, Annika Schneider, Karl Kramer, Mar Abril-Gil, Thomas A. Hopf, Leonie Reichart, Lin Chen, Fynn M. Hansen, Severin Lechner, Patroklos Samaras, Stephan Eckert, Ludwig Lautenbacher, Maria Reinecke, Firas Hamood, Polina Prokofeva, Larsen Vornholz, Chiara Falcomatà, Madeleine Dorsch, Eva Ayla Schröder, Anton Jan Venhuizen, Stephanie Wilhelm, Guillaume Médard, Gabriele Stoehr, Jürgen Ruland, Barbara M. Grüner, Dieter Saur, Maike Buchner, Benjamin Ruprecht, Hannes Hahne, Matthew The, Mathias Wilhelm, Bernhard Küster
Abstract
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.