| Autor: |
Haipeng Liu, Hang Su, Fei Wang, Yifang Dang, Yijiu Ren, Shenyi Yin, Huinan Lu, Hang Zhang, Jun Wu, Zhu Xu, Mengge Zheng, Jiani Gao, Yajuan Cao, Junfang Xu, Li Chen, Xiangyang Wu, Mingtong Ma, Long Xu, Fang Wang, Jianxia Chen, Chunxia Su, Chunyan Wu, Huikang Xie, Jijie Gu, Jianzhong Jeff Xi, Baoxue Ge, Yiyan Fei, Chang Chen |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Cell Reports, Vol 42, Iss 3, Pp 112275- (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2023.112275 |
| Popis: |
Summary: Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8+ T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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