An Integrative Proteome-Based Pharmacologic Characterization and Therapeutic Strategy Exploration of SAHA in Solid Malignancies

Targeting histone epigenetic modification is an important strategy for anticancer therapy. Histone deacetylase inhibitors (HDACis) have been clinically approved in the treatment of diverse hematological cancers, but mechanisms of drug resistance and poor therapeutic efficacy in solid malignancies remain largely unknown. In this study, we applied a mass spectrometry-based quantitative proteomic strategy to investigate the molecular differences in HDACi vorinostat (SAHA) sensitive and resistant cell lines. The proteomic results revealed that the glycolysis pathway was highly enriched after vorinostat treatment in the resistant cell line, leading to the prediction of a new drug combination, SAHA and hexokinase inhibitor (2-deoxyglucose). The efficacy of this combination was further verified in several solid tumor cell lines. Quantitative proteomics revealed that alterations in the transcription process and protein homeostasis could play roles in the synergetic utilization of these two compounds. Our study showed the application of proteomics in elucidating the drug mechanism and predicting drug combination and the potential of expanding the utilization of HDACi.

靶向组蛋白表观遗传修饰是抗肿瘤治疗的重要策略。组蛋白去乙酰化酶抑制剂（Histone deacetylase inhibitors, HDACis）已被临床批准用于多种血液系统恶性肿瘤的治疗，但实体瘤中的耐药机制及治疗疗效欠佳的问题仍未被充分阐明。本研究采用基于质谱的定量蛋白质组学策略，探究组蛋白去乙酰化酶抑制剂伏立诺他（vorinostat, SAHA）敏感与耐药细胞系的分子差异。蛋白质组学结果显示，耐药细胞系经伏立诺他处理后，糖酵解通路显著富集，由此预测得到全新的药物联合方案：SAHA与己糖激酶抑制剂（hexokinase inhibitor, 2-脱氧葡萄糖，2-deoxyglucose）。该联合方案的疗效在多个实体瘤细胞系中得到进一步验证。定量蛋白质组学分析揭示，转录过程与蛋白质稳态的改变可能参与了这两种化合物的协同作用。本研究证实了蛋白质组学在阐明药物作用机制、预测药物联合方案中的应用价值，以及拓展组蛋白去乙酰化酶抑制剂临床应用潜力的可能性。