Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors
Abstract 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 potenti...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-024-01775-2 |
| _version_ | 1797199124023476224 |
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| author | Yijun Cheng Yuting Dai Hao Tang Xingyu Lu Jing Xie Wanqun Xie Qianqian Zhang Yanting Liu Shaojian Lin Hong Yao Hanbing Shang Kun Yang Hongyi Liu Xuefeng Wu Jianming Zhang Xun Zhang Li Xue Zhe Bao Wu |
| author_facet | Yijun Cheng Yuting Dai Hao Tang Xingyu Lu Jing Xie Wanqun Xie Qianqian Zhang Yanting Liu Shaojian Lin Hong Yao Hanbing Shang Kun Yang Hongyi Liu Xuefeng Wu Jianming Zhang Xun Zhang Li Xue Zhe Bao Wu |
| author_sort | Yijun Cheng |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-24T07:10:46Z |
| format | Article |
| id | doaj.art-64e201bafc6c4ecf89755a6629ebc323 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-04-24T07:10:46Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-64e201bafc6c4ecf89755a6629ebc3232024-04-21T11:33:36ZengBMCActa Neuropathologica Communications2051-59602024-04-0112111210.1186/s40478-024-01775-2Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumorsYijun Cheng0Yuting Dai1Hao Tang2Xingyu Lu3Jing Xie4Wanqun Xie5Qianqian Zhang6Yanting Liu7Shaojian Lin8Hong Yao9Hanbing Shang10Kun Yang11Hongyi Liu12Xuefeng Wu13Jianming Zhang14Xun Zhang15Li Xue16Zhe Bao Wu17Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineShanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Neurosurgery, Xinhua Hospital, Shanghai Jiao Tong University School of MedicineNational Research Center for Translational Medicine (Shanghai), State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Neurosurgery, Nanjing Brain Hospital, Nanjing Medical UniversityDepartment of Neurosurgery, Nanjing Brain Hospital, Nanjing Medical UniversityCenter for Immune-Related DiseasesShanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineNational Research Center for Translational Medicine (Shanghai), State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineNeuroendocrine Research Laboratory, Massachusetts General Hospital and Harvard Medical SchoolDepartment of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineAbstract 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.https://doi.org/10.1186/s40478-024-01775-2PitNETsHigh-throughput screeningHDACIsPanobinostatNrf2 |
| spellingShingle | Yijun Cheng Yuting Dai Hao Tang Xingyu Lu Jing Xie Wanqun Xie Qianqian Zhang Yanting Liu Shaojian Lin Hong Yao Hanbing Shang Kun Yang Hongyi Liu Xuefeng Wu Jianming Zhang Xun Zhang Li Xue Zhe Bao Wu Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors Acta Neuropathologica Communications PitNETs High-throughput screening HDACIs Panobinostat Nrf2 |
| title | Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors |
| title_full | Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors |
| title_fullStr | Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors |
| title_full_unstemmed | Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors |
| title_short | Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors |
| title_sort | therapeutic potential of targeting nrf2 by panobinostat in pituitary neuroendocrine tumors |
| topic | PitNETs High-throughput screening HDACIs Panobinostat Nrf2 |
| url | https://doi.org/10.1186/s40478-024-01775-2 |
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