通过临床研究发现，三阴性乳腺癌（TNBC）患者因治疗选择有限而预后较差、复发率较高。本研究旨在确定泛素化酶抑制剂帕诺比尼斯他（panobinostat）在TNBC中的作用机制，并为针对这种侵袭性疾病的有效药物组合提供理论依据。通过对CL TNBC（MDA-MB-231）细胞中未经处理或经帕诺比尼斯他处理的RNA测序分析，鉴定了差异表达基因。并对其他CL TNBC细胞中的基因表达进行了分析和验证。肿瘤异种移植模型用于测试帕诺比尼斯他单独或与吉非替尼（一种EGFR酪氨酸激酶抑制剂）联合的抗肿瘤活性。帕诺比尼斯他强烈抑制了所有经过测试的TNBC细胞的增殖，并诱导细胞凋亡。然而，在CL TNBC细胞中，该组织平衡酶抑制剂显著增强了HER3的表达，HER3与EGFR相互作用，激活了双方的受体和Akt信号通路。帕诺比尼斯他与吉非替尼联合治疗在体外和体内能够协同抑制CL TNBC细胞的增殖，并促进细胞凋亡。HER3的上调降低了帕诺比尼斯他在CL TNBC中的疗效。与帕诺比尼斯他联合治疗HER3的失活，是应对CL TNBC的一种实用方法。 © 2023. Nature Publishing Group UK.

Patients with triple-negative breast cancer (TNBC) have a poor prognosis and high relapse rate due to limited therapeutic options. This study was conducted to determine the mechanisms of action of panobinostat, a pan-inhibitor of histone deacetylase (HDAC) and FDA-approved medication for multiple myeloma, in TNBC and to provide a rationale for effective drug combinations against this aggressive disease. RNA sequencing analyses of the claudin-low (CL) TNBC (MDA-MB-231) cells untreated or treated with panobinostat were performed to identify the differentially expressed genes. Adaptive alterations in gene expression were analyzed and validated in additional CL TNBC cells. Tumor xenograft models were used to test the in vivo antitumor activity of panobinostat alone or its combinations with gefitinib, an EGFR-tyrosine kinase inhibitor (TKI). Panobinostat potently inhibited proliferation and induced apoptosis in all TNBC cells tested. However, in CL TNBC cells, this HDAC inhibitor markedly enhanced expression of HER3, which interacted with EGFR to activate both receptors and Akt signaling pathways. Combinations of panobinostat and gefitinib synergistically suppressed CL TNBC cell proliferation and promoted apoptosis in vitro and in vivo. Upregulation of HER3 compromises the efficacy of panobinostat in CL TNBC. Inactivation of HER3 combined with panobinostat represents a practical approach to combat CL TNBC.© 2023. Nature Publishing Group UK.