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

被引：36

作者：

Zecha, Jana ^{[1
,2
]}

Bayer, Florian P. ^{[1
]}

Wiechmann, Svenja ^{[1
,2
]}

Woortman, Julia ^{[1
]}

Berner, Nicola ^{[1
,2
]}

Mueller, Julian ^{[1
]}

Schneider, Annika ^{[1
]}

Kramer, Karl ^{[1
]}

Abril-Gil, Mar ^{[3
]}

Hopf, Thomas ^{[4
]}

Reichart, Leonie ^{[4
]}

Chen, Lin ^{[1
]}

Hansen, Fynn M. ^{[1
,10
]}

Lechner, Severin ^{[1
]}

Samaras, Patroklos ^{[1
]}

Eckert, Stephan ^{[1
,2
]}

Lautenbacher, Ludwig ^{[1
]}

Reinecke, Maria ^{[1
]}

Hamood, Firas ^{[1
]}

Prokofeva, Polina ^{[1
]}

Vornholz, Larsen ^{[3
]}

Falcomata, Chiara ^{[2
,5
]}

Dorsch, Madeleine ^{[6
,7
]}

Schroeder, Ayla ^{[4
]}

Venhuizen, Anton ^{[1
]}

Wilhelm, Stephanie ^{[1
]}

Medard, Guillaume ^{[1
]}

Stoehr, Gabriele ^{[4
]}

Ruland, Juergen ^{[2
,3
,8
,9
]}

Gruener, Barbara M. ^{[6
,7
]}

Saur, Dieter ^{[2
,5
]}

Buchner, Maike ^{[3
]}

Ruprecht, Benjamin ^{[1
]}

Hahne, Hannes ^{[4
]}

The, Matthew ^{[1
]}

Wilhelm, Mathias ^{[1
]}

Kuster, Bernhard ^{[1
,2
]}

机构：

[1] Tech Univ Munich, Sch Life Sci, Dept Mol Life Sci, Prote & Bioanalyt, D-85354 Freising Weihenstephan, Germany

[2] German Canc Consortium, Partner Site Munich, D-80336 Munich, Germany

[3] Tech Univ Munich, Inst Clin Chem & Pathobiochem, Sch Med, Klinikum Rechts Isar, D-81675 Munich, Germany

[4] OmicScouts GmbH, D-85354 Freising Weihenstephan, Germany

[5] Tech Univ Munich, Inst Expt Canc Therapy, Sch Med, Klinikum Rechts Isar, D-80336 Munich, Germany

[6] Univ Hosp Essen, West German Canc Ctr, Dept Med Oncol, D-45147 Essen, Germany

[7] Partner Site Univ Hosp Essen, German Canc Consortium DKTK, D-45147 Essen, Germany

[8] German Ctr Infect Res DZIF, Partner Site Munich, D-81675 Munich, Germany

[9] Ctr Translat Canc Res TranslaTUM, D-81675 Munich, Germany

[10] Max Planck Inst Biochem, Dept Prote & Signal Transduct, D-82152 Martinsried, Germany

来源：

SCIENCE | 2023年 / 380卷 / 6640期

基金：

欧洲研究理事会; 欧盟地平线“2020”;

关键词：

LIPID RAFT; RECEPTOR; TRASTUZUMAB; INHIBITION; PERTUZUMAB; MECHANISM; REVEALS; TARGET; CELLS;

D O I：

10.1126/science.ade3925

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页码：93 / 101

页数：9

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