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

Bing-bing Hao1, Ke Ma2, Jun-yu Xu1,3, Ru-feng Fan1,4, Wen-si Zhao5, Xing-long Jia1,6, Lin-hui Zhai1,3, SangKyu Lee7, Dong Xie5, Min-jia Tan1,2,3,4
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
Correspondence to: Jun-yu Xu:, Dong Xie:, Min-jia Tan:,
DOI: 10.1038/s41401-024-01236-5
Received: 11 November 2023
Accepted: 29 January 2024
Advance online: 21 February 2024


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.

Keywords: solid tumor; histone deacetylase inhibitor; vorinostat (SAHA); drug resistance; proteomics

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