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

Jana Zecha; Florian P. Bayer; Svenja Wiechmann; Julia Woortman; Nicola Berner; Julian Müller; Annika Schneider; Karl Kramer; Mar Abril-Gil; Thomas 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; Ayla Schröder; Anton 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 Kuster

doi:10.1126/science.ade3925

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

Jana Zecha, Florian P. Bayer, Svenja Wiechmann, Julia Woortman, Nicola Berner, Julian Müller, Annika Schneider, Karl Kramer, Mar Abril-Gil, Thomas Hopf, Leonie Reichart, Lin Chen, Fynn M. Hansen, Severin Lechner, Patroklos Samaras, Stephan Eckert, Ludwig Lautenbacher, Maria Reinecke, Firas Hamood, Polina ProkofevaLarsen Vornholz, Chiara Falcomatà, Madeleine Dorsch, Ayla Schröder, Anton 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 Kuster

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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.

Original language	English
Pages (from-to)	93-101
Number of pages	9
Journal	Science
Volume	380
Issue number	6640
DOIs	https://doi.org/10.1126/science.ade3925
State	Published - 7 Apr 2023

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Zecha, J., Bayer, F. P., Wiechmann, S., Woortman, J., Berner, N., Müller, J., Schneider, A., Kramer, K., Abril-Gil, M., Hopf, T., Reichart, L., Chen, L., Hansen, F. M., Lechner, S., Samaras, P., Eckert, S., Lautenbacher, L., Reinecke, M., Hamood, F., ... Kuster, B. (2023). Decrypting drug actions and protein modifications by dose- and time-resolved proteomics. Science, 380(6640), 93-101. https://doi.org/10.1126/science.ade3925

@article{490535681a124ed89d5ce6cd223d34b2,

title = "Decrypting drug actions and protein modifications by dose- and time-resolved proteomics",

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.",

author = "Jana Zecha and Bayer, {Florian P.} and Svenja Wiechmann and Julia Woortman and Nicola Berner and Julian M{\"u}ller and Annika Schneider and Karl Kramer and Mar Abril-Gil and Thomas Hopf and Leonie Reichart and Lin Chen and Hansen, {Fynn M.} and Severin Lechner and Patroklos Samaras and Stephan Eckert and Ludwig Lautenbacher and Maria Reinecke and Firas Hamood and Polina Prokofeva and Larsen Vornholz and Chiara Falcomat{\`a} and Madeleine Dorsch and Ayla Schr{\"o}der and Anton Venhuizen and Stephanie Wilhelm and Guillaume M{\'e}dard and Gabriele Stoehr and J{\"u}rgen Ruland and Gr{\"u}ner, {Barbara M.} and Dieter Saur and Maike Buchner and Benjamin Ruprecht and Hannes Hahne and Matthew The and Mathias Wilhelm and Bernhard Kuster",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",

year = "2023",

month = apr,

day = "7",

doi = "10.1126/science.ade3925",

language = "English",

volume = "380",

pages = "93--101",

journal = "Science",

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Zecha, J, Bayer, FP, Wiechmann, S, Woortman, J, Berner, N, Müller, J, Schneider, A, Kramer, K, Abril-Gil, M, Hopf, T, Reichart, L, Chen, L, Hansen, FM, Lechner, S, Samaras, P, Eckert, S, Lautenbacher, L, Reinecke, M, Hamood, F, Prokofeva, P, Vornholz, L, Falcomatà, C, Dorsch, M, Schröder, A, Venhuizen, A, Wilhelm, S, Médard, G, Stoehr, G, Ruland, J, Grüner, BM, Saur, D, Buchner, M, Ruprecht, B, Hahne, H, The, M, Wilhelm, M & Kuster, B 2023, 'Decrypting drug actions and protein modifications by dose- and time-resolved proteomics', Science, vol. 380, no. 6640, pp. 93-101. https://doi.org/10.1126/science.ade3925

TY - JOUR

T1 - Decrypting drug actions and protein modifications by dose- and time-resolved proteomics

AU - Zecha, Jana

AU - Bayer, Florian P.

AU - Wiechmann, Svenja

AU - Woortman, Julia

AU - Berner, Nicola

AU - Müller, Julian

AU - Schneider, Annika

AU - Kramer, Karl

AU - Abril-Gil, Mar

AU - Hopf, Thomas

AU - Reichart, Leonie

AU - Chen, Lin

AU - Hansen, Fynn M.

AU - Lechner, Severin

AU - Samaras, Patroklos

AU - Eckert, Stephan

AU - Lautenbacher, Ludwig

AU - Reinecke, Maria

AU - Hamood, Firas

AU - Prokofeva, Polina

AU - Vornholz, Larsen

AU - Falcomatà, Chiara

AU - Dorsch, Madeleine

AU - Schröder, Ayla

AU - Venhuizen, Anton

AU - Wilhelm, Stephanie

AU - Médard, Guillaume

AU - Stoehr, Gabriele

AU - Ruland, Jürgen

AU - Grüner, Barbara M.

AU - Saur, Dieter

AU - Buchner, Maike

AU - Ruprecht, Benjamin

AU - Hahne, Hannes

AU - The, Matthew

AU - Wilhelm, Mathias

AU - Kuster, Bernhard

PY - 2023/4/7

Y1 - 2023/4/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85152012772&partnerID=8YFLogxK

U2 - 10.1126/science.ade3925

DO - 10.1126/science.ade3925

M3 - Article

C2 - 36926954

AN - SCOPUS:85152012772

SN - 0036-8075

VL - 380

SP - 93

EP - 101

JO - Science

JF - Science

IS - 6640

ER -

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

Abstract

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