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.