Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197# Ruijin er road, Shanghai, 200025, China.
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Acta Neuropathol Commun. 2024 Apr 18;12(1):61. doi: 10.1186/s40478-024-01775-2.
We aimed to identify the druggable cell-intrinsic vulnerabilities and target-based drug therapies for PitNETs using the high-throughput drug screening (HTS) and genomic sequencing methods. We examined 9 patient-derived PitNET primary cells in HTS. Based on the screening results, the potential target genes were analyzed with genomic sequencing from a total of 180 PitNETs. We identified and verified one of the most potentially effective drugs, which targeted the Histone deacetylases (HDACs) both in in vitro and in vivo PitNET models. Further RNA sequencing revealed underlying molecular mechanisms following treatment with the representative HDACs inhibitor, Panobinostat. The HTS generated a total of 20,736 single-agent dose responses which were enriched among multiple inhibitors for various oncogenic targets, including HDACs, PI3K, mTOR, and proteasome. Among these drugs, HDAC inhibitors (HDACIs) were, on average, the most potent drug class. Further studies using in vitro, in vivo, and isolated PitNET primary cell models validated HDACIs, especially Panobinostat, as a promising therapeutic agent. Transcriptional surveys revealed substantial alterations to the Nrf2 signaling following Panobinostat treatment. Moreover, Nrf2 is highly expressed in PitNETs. The combination of Panobinostat and Nrf2 inhibitor ML385 had a synergistic effect on PitNET suppression. The current study revealed a class of effective anti-PitNET drugs, HDACIs, based on the HTS and genomic sequencing. One of the representative compounds, Panobinostat, may be a potential drug for PitNET treatment via Nrf2-mediated redox modulation. Combination of Panobinostat and ML385 further enhance the effectiveness for PitNET treatment.
我们旨在通过高通量药物筛选 (HTS) 和基因组测序方法，确定用于胰腺神经内分泌肿瘤 (PitNET) 的可药物化细胞内在脆弱性和基于靶标的药物治疗方法。我们在 HTS 中检查了 9 个患者来源的 PitNET 原代细胞。基于筛选结果，通过对总共 180 个 PitNET 的基因组测序分析潜在的靶标基因。我们鉴定并验证了一种最有效的潜在药物，该药物针对体外和体内 PitNET 模型中的组蛋白去乙酰化酶 (HDACs)。进一步的 RNA 测序揭示了在使用代表性的 HDAC 抑制剂 Panobinostat 治疗后潜在的分子机制。HTS 总共产生了 20,736 种单药剂量反应，这些反应在针对各种致癌靶标的多种抑制剂中富集，包括 HDACs、PI3K、mTOR 和蛋白酶体。在这些药物中，HDAC 抑制剂 (HDACIs) 平均是最有效的药物类别。使用体外、体内和分离的 PitNET 原代细胞模型的进一步研究验证了 HDACIs，特别是 Panobinostat，作为一种有前途的治疗剂。转录调查显示，Panobinostat 治疗后 Nrf2 信号发生了实质性改变。此外，Nrf2 在 PitNETs 中高度表达。Panobinostat 和 Nrf2 抑制剂 ML385 的组合对 PitNET 抑制具有协同作用。本研究基于 HTS 和基因组测序，揭示了一类有效的抗 PitNET 药物，即 HDACIs。代表性化合物之一 Panobinostat 可能通过 Nrf2 介导的氧化还原调节成为治疗 PitNET 的潜在药物。Panobinostat 和 ML385 的联合进一步增强了治疗 PitNET 的效果。
