药物学增强cGAS激活，通过增强抗肿瘤免疫力，增强化疗敏感性。
Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity.
发表日期：2023 Mar 20
作者：
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
来源：
Cell Reports
摘要：
增强化疗敏感性是癌症治疗中最大的未满足医疗需求之一。Cyclic GMP-AMP合成酶（cGAS）将铂化学治疗引起的基因组不稳定性与I类干扰素（IFN）反应联系起来。在此，我们利用高通量小分子微阵列筛选cGAS相互作用化合物的方法，发现一个双重抑制血管内皮生长因子受体和成纤维细胞生长因子受体的药物–brivanib，被鉴定为一种cGAS调节剂。Brivanib显著增强了铂处理后的肿瘤细胞中cGAS介导的I类干扰素反应。在机制上，Brivanib直接靶向cGAS并增强其DNA结合亲和力。重要的是，Brivanib与顺铂在肿瘤控制中协同作用，通过增强肿瘤内cGAS依赖性的CD8+ T细胞反应，这在一个患者来源的肿瘤样细胞簇模型中得到了进一步验证。综上所述，我们的研究发现cGAS是brivanib的一个前所未有的靶点，并为将brivanib与铂类化学治疗剂结合使用提供了理论依据。版权所有 © 2023 版权所有者。由Elsevier公司发表。保留所有权利。
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.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.