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

Zecha, Jana; Bayer, Florian P; Wiechmann, Svenja; Woortman, Julia; Berner, Nicola; Müller, 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; Falcomatà, Chiara; Dorsch, Madeleine; Schröder, Ayla; Venhuizen, Anton; Wilhelm, Stephanie; Médard, Guillaume; Stoehr, Gabriele; Ruland, Jürgen; Grüner, Barbara M; Saur, Dieter; Buchner, Maike; Ruprecht, Benjamin; Hahne, Hannes; The, Matthew; Wilhelm, Mathias; Kuster, Bernhard     «

Zecha, Jana; Bayer, Florian P; Wiechmann, Svenja; Woortman, Julia; Berner, Nicola; Müller, 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; Falcomatà, Chiara; Dorsch, Madeleine; Schröder, Ayla; Venhuizen, Anton; Wilhelm, Stephanie; Médard, Guillaume; Stoehr, Gabriele; Ruland, Jürgen; Gr...     »

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.      «

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 identify...     »