我们旨在使用高通量药物筛选(HTS)和基因组测序方法确定PitNETs的可药用细胞固有漏洞和基于靶标的药物治疗。我们检查了HTS中9个患者来源的PitNET原代细胞。根据筛选结果,通过基因组测序分析了180个PitNETs的潜在靶基因.我们确定并验证了最有效的药物之一,在体外和体内PitNET模型中均靶向组蛋白脱乙酰酶(HDACs)。进一步的RNA测序揭示了用代表性的HDACs抑制剂治疗后的潜在分子机制,Panobinostat.HTS产生了总共20,736种单药剂量反应,这些反应在多种致癌靶标的多种抑制剂中富集。包括HDAC,PI3K,mTOR,和蛋白酶体。在这些药物中,HDAC抑制剂(HDACIs),平均而言,最有效的药物类别。使用体外的进一步研究,在体内,和隔离的PitNET主细胞模型验证HDACIs,尤其是Panobinostat,作为一种有前途的治疗剂。转录调查显示,Panobinostat治疗后Nrf2信号发生了实质性变化。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。目前的研究揭示了一类有效的抗PitNET药物,HDACIs,基于HTS和基因组测序。代表性化合物之一,Panobinostat,可能是通过Nrf2介导的氧化还原调节PitNET治疗的潜在药物。Panobinostat和ML385的组合进一步增强了PitNET治疗的有效性。
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.