中国科学院上海药物研究所Min-jia Tan，Jun-yu Xu和同济大学医学院Dong Xie共同合作，近期取得重要工作进展。他们通过组蛋白去乙酰化酶抑制剂耐药实体瘤的蛋白质组学分析揭示出实体瘤的耐药特征及潜在的药物组合。相关研究成果2024年2月21日在线发表于《中国药理学学报》杂志上。

据介绍，组蛋白脱乙酰酶抑制剂（HDACi）是癌症治疗的重要药物，但实体瘤治疗的耐药机制不明确，极大地限制了其临床应用。

研究人员使用基于串联质量标签（TMT）的定量蛋白质组学策略，在HDACi敏感和耐药细胞系中进行了HDACi干扰蛋白质组学和磷酸蛋白质组学分析。研究人员发现，对肿瘤发生至关重要的核糖体生物发生蛋白MRTO4、PES1、WDR74和NOP16可能调节肿瘤对HDACi的敏感性。通过将HDACi干扰的蛋白质特征与先前报道的蛋白质组学和药物敏感性数据相结合，研究人员预测并验证了一系列可能增强HDACi在不同实体瘤中敏感性的药物组合对。功能磷酸蛋白质组学分析进一步确定激酶PDK1和ROCK是潜在的HDACi耐药性特征。

总之，这项研究揭示了潜在的HDACi耐药性特征，并可能提供有希望的药物组合策略来减弱实体瘤对HDACi的耐药性。

附：英文原文

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

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

Issue&Volume: 2024-02-21

Abstract: 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.

DOI: 10.1038/s41401-024-01236-5

Source: https://www.nature.com/articles/s41401-024-01236-5