Pharmacologic inhibition of CSF-1R suppresses intrinsic tumor cell growth in osteosarcoma with CSF-1R overexpression
Abstract Background Osteosarcoma is the most common primary malignant bone tumor affecting children and young adults. Metastatic osteosarcoma has poor prognosis and represents a significant unmet medical need in clinical settings. The CSF-1/CSF-1R signaling pathway is essential for the physiological...
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BMC
2025-08-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06920-6 |
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| author | Cheng Dai Bin Shen Shenyan Liu Cong Li Shuqun Yang Jie Wang Jie Zhang Manqi Liu Zhixuan Zhu Wan Shi Qi Zhang Zhui Chen Nannan Zhang |
| author_facet | Cheng Dai Bin Shen Shenyan Liu Cong Li Shuqun Yang Jie Wang Jie Zhang Manqi Liu Zhixuan Zhu Wan Shi Qi Zhang Zhui Chen Nannan Zhang |
| author_sort | Cheng Dai |
| collection | DOAJ |
| description | Abstract Background Osteosarcoma is the most common primary malignant bone tumor affecting children and young adults. Metastatic osteosarcoma has poor prognosis and represents a significant unmet medical need in clinical settings. The CSF-1/CSF-1R signaling pathway is essential for the physiological functions of myeloid lineage cells, including osteoclasts and monocytes/macrophages. The purpose of this study is to investigate the role of CSF-1R in osteosarcoma pathogenesis and the therapeutical potentiality of CSF-1R inhibitor for osteosarcoma patients. Methods CSF-1, CSF-1R, and IL-34 expression across cancer types were evaluated using public database. Immunohistochemistry (IHC) was utilized to analyze human tissue microarray samples of osteosarcoma. We then investigated the anti-tumor effect and the mechanisms of action of pharmacologic inhibition of CSF-1R activity by pimicotinib (ABSK021), a highly potent and selective small molecule inhibitor of CSF-1R, in osteosarcoma models both in vitro and in vivo. Results IHC analysis of human tissue microarray samples revealed a high prevalence of CSF-1R overexpression in osteosarcoma patient samples. ABSK021 effectively inhibited CSF-1R signaling and the proliferation of osteosarcoma cells with high expression of CSF-1R, by inducing cell cycle arrest and apoptosis. In contrast, it had a marginal effect on osteosarcoma cell lines with low CSF-1R expression. In animal studies, ABSK021 demonstrated strong anti-tumor activity in both a syngeneic mouse osteosarcoma model and osteosarcoma patient sample-derived xenograft (PDX) models with CSF-1R overexpression. The analysis of endpoint tumor samples revealed downregulation of CSF-1R signaling and proliferative marker Ki67, along with the increase of apoptotic marker cleaved caspase-3, confirming the on-target effects of ABSK021 in vivo. Furthermore, combining ABSK021 with standard-of-care chemotherapy showed enhanced anti-tumor activity both in vitro and in vivo. Conclusions These findings conclusively demonstrated that pharmacological inhibition of CSF-1R activity by ABSK021 resulted in significant anti-tumor effects in preclinical osteosarcoma models with CSF-1R overexpression. The high prevalence of CSF-1R expression observed in osteosarcoma patient samples highlights the potential clinical use of ABSK021, either as a monotherapy or in combination with chemotherapy, as a promising therapeutic strategy for osteosarcoma patients with CSF-1R as a potential predictive biomarker. |
| format | Article |
| id | doaj-art-7a2c97145cd54a1b8ccc01d21647e877 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-7a2c97145cd54a1b8ccc01d21647e8772025-08-20T03:43:30ZengBMCJournal of Translational Medicine1479-58762025-08-0123111610.1186/s12967-025-06920-6Pharmacologic inhibition of CSF-1R suppresses intrinsic tumor cell growth in osteosarcoma with CSF-1R overexpressionCheng Dai0Bin Shen1Shenyan Liu2Cong Li3Shuqun Yang4Jie Wang5Jie Zhang6Manqi Liu7Zhixuan Zhu8Wan Shi9Qi Zhang10Zhui Chen11Nannan Zhang12Abbisko Therapeutics Co., LtdAbbisko Therapeutics Co., LtdAbbisko Therapeutics Co., LtdAbbisko Therapeutics Co., LtdAbbisko Therapeutics Co., LtdAbbisko Therapeutics Co., LtdAbbisko Therapeutics Co., LtdAbbisko Therapeutics Co., LtdAbbisko Therapeutics Co., LtdAbbisko Therapeutics Co., LtdAbbisko Therapeutics Co., LtdAbbisko Therapeutics Co., LtdAbbisko Therapeutics Co., LtdAbstract Background Osteosarcoma is the most common primary malignant bone tumor affecting children and young adults. Metastatic osteosarcoma has poor prognosis and represents a significant unmet medical need in clinical settings. The CSF-1/CSF-1R signaling pathway is essential for the physiological functions of myeloid lineage cells, including osteoclasts and monocytes/macrophages. The purpose of this study is to investigate the role of CSF-1R in osteosarcoma pathogenesis and the therapeutical potentiality of CSF-1R inhibitor for osteosarcoma patients. Methods CSF-1, CSF-1R, and IL-34 expression across cancer types were evaluated using public database. Immunohistochemistry (IHC) was utilized to analyze human tissue microarray samples of osteosarcoma. We then investigated the anti-tumor effect and the mechanisms of action of pharmacologic inhibition of CSF-1R activity by pimicotinib (ABSK021), a highly potent and selective small molecule inhibitor of CSF-1R, in osteosarcoma models both in vitro and in vivo. Results IHC analysis of human tissue microarray samples revealed a high prevalence of CSF-1R overexpression in osteosarcoma patient samples. ABSK021 effectively inhibited CSF-1R signaling and the proliferation of osteosarcoma cells with high expression of CSF-1R, by inducing cell cycle arrest and apoptosis. In contrast, it had a marginal effect on osteosarcoma cell lines with low CSF-1R expression. In animal studies, ABSK021 demonstrated strong anti-tumor activity in both a syngeneic mouse osteosarcoma model and osteosarcoma patient sample-derived xenograft (PDX) models with CSF-1R overexpression. The analysis of endpoint tumor samples revealed downregulation of CSF-1R signaling and proliferative marker Ki67, along with the increase of apoptotic marker cleaved caspase-3, confirming the on-target effects of ABSK021 in vivo. Furthermore, combining ABSK021 with standard-of-care chemotherapy showed enhanced anti-tumor activity both in vitro and in vivo. Conclusions These findings conclusively demonstrated that pharmacological inhibition of CSF-1R activity by ABSK021 resulted in significant anti-tumor effects in preclinical osteosarcoma models with CSF-1R overexpression. The high prevalence of CSF-1R expression observed in osteosarcoma patient samples highlights the potential clinical use of ABSK021, either as a monotherapy or in combination with chemotherapy, as a promising therapeutic strategy for osteosarcoma patients with CSF-1R as a potential predictive biomarker.https://doi.org/10.1186/s12967-025-06920-6CSF-1RPimicotinibABSK021Osteosarcoma |
| spellingShingle | Cheng Dai Bin Shen Shenyan Liu Cong Li Shuqun Yang Jie Wang Jie Zhang Manqi Liu Zhixuan Zhu Wan Shi Qi Zhang Zhui Chen Nannan Zhang Pharmacologic inhibition of CSF-1R suppresses intrinsic tumor cell growth in osteosarcoma with CSF-1R overexpression Journal of Translational Medicine CSF-1R Pimicotinib ABSK021 Osteosarcoma |
| title | Pharmacologic inhibition of CSF-1R suppresses intrinsic tumor cell growth in osteosarcoma with CSF-1R overexpression |
| title_full | Pharmacologic inhibition of CSF-1R suppresses intrinsic tumor cell growth in osteosarcoma with CSF-1R overexpression |
| title_fullStr | Pharmacologic inhibition of CSF-1R suppresses intrinsic tumor cell growth in osteosarcoma with CSF-1R overexpression |
| title_full_unstemmed | Pharmacologic inhibition of CSF-1R suppresses intrinsic tumor cell growth in osteosarcoma with CSF-1R overexpression |
| title_short | Pharmacologic inhibition of CSF-1R suppresses intrinsic tumor cell growth in osteosarcoma with CSF-1R overexpression |
| title_sort | pharmacologic inhibition of csf 1r suppresses intrinsic tumor cell growth in osteosarcoma with csf 1r overexpression |
| topic | CSF-1R Pimicotinib ABSK021 Osteosarcoma |
| url | https://doi.org/10.1186/s12967-025-06920-6 |
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