Proteomics analysis of histone deacetylase inhibitor-resistant solid tumors reveals resistant signatures and potential drug combinations  

作　　者：Bing-bing Hao Ke Ma Jun-yu Xu Ru-feng Fan Wen-si Zhao Xing-long Jia Lin-hui Zhai SangKyu Lee Dong Xie Min-jia Tan 

机构地区：[1]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [2]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing,210023,China [3]Zhongshan Institute for Drug Discovery,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Zhongshan,528400,China [4]University of Chinese Academy of Sciences,Beijing,100049,China [5]Department of Thoracic Surgery,Shanghai Pulmonary Hospital,School of Medicine,Tongji University,Shanghai,200433,China [6]Department of Pharmacology,School of Pharmacy,Fudan University,Shanghai,201203,China [7]College of Pharmacy and Research Institute of Pharmaceutical Sciences,Kyungpook National University,Daegu,Republic of Korea

出　　处：《Acta Pharmacologica Sinica》2024年第6期1305-1315,共11页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(32071432,32171434,82272943,32322048);the Youth Science and Technology Talents in Shanghai Sail Plan of China(21YF1456000);Young Elite Scientists Sponsorship Program by CAST(2022QNRC001);Shanghai Rising-Star Program(22QA1411100);the Youth Innovation Promotion Association(CAS2021276);the Sanofi Scholarship Program,Shanghai Committee of Science and Technology,China(21Y11913400);Guangdong High-level New R&D Institute,China(2019B090904008);Guangdong High-level Innovative Research Institute,China(2021B0909050003).

摘　　要：Histone deacetylase inhibitors(HDACis)are important drugs for cancer therapy,but the indistinct resistant mechanisms of solid tumor therapy greatly limit their clinical application.In this study we conducted HDACi-perturbated proteomics and phosphoproteomics analyses in HDACi-sensitive and-resistant cell lines using a tandem mass tag(TMT)-based quantitative proteomic strategy.We found that the ribosome biogenesis proteins MRTO4,PES1,WDR74 and NOP16 vital to tumorigenesis might regulate the tumor sensitivity to HDACi.By integrating HDACi-perturbated protein signature with previously reported proteomics and drug sensitivity data,we predicted and validated a series of drug combination pairs potentially to enhance the sensitivity of HDACi in diverse solid tumor.Functional phosphoproteomic analysis further identified the kinase PDK1 and ROCK as potential HDACi-resistant signatures.Overall,this study reveals the potential HDACi-resistant signatures and may provide promising drug combination strategies to attenuate the resistance of solid tumor to HDACi.

关 键 词：solid tumor histone deacetylase inhibitor vorinostat(SAHA) drug resistance PROTEOMICS 

分 类 号：R96[医药卫生—药理学]