2. Academic Validation
  3. Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity

Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity

  • Cell Rep. 2023 Mar 20;42(3):112275. doi: 10.1016/j.celrep.2023.112275.
Haipeng Liu 1,  Hang Su 2,  Fei Wang 3,  Yifang Dang 4,  Yijiu Ren 2,  Shenyi Yin 5,  Huinan Lu 6,  Hang Zhang 7,  Jun Wu 8,  Zhu Xu 9,  Mengge Zheng 10,  Jiani Gao 2,  Yajuan Cao 10,  Junfang Xu 10,  Li Chen 10,  Xiangyang Wu 11,  Mingtong Ma 3,  Long Xu 2,  Fang Wang 2,  Jianxia Chen 11,  Chunxia Su 12,  Chunyan Wu 13,  Huikang Xie 13,  Jijie Gu 14,  Jianzhong Jeff Xi 5,  Baoxue Ge 15,  Yiyan Fei 16,  Chang Chen 17
Affiliations

Affiliations

  • 1 Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai HUASHEN Institute of Microbes and Infections, Shanghai 200052, China. Electronic address: [email protected].
  • 2 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • 3 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • 4 Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai HUASHEN Institute of Microbes and Infections, Shanghai 200052, China.
  • 5 College of Future Technology, Peking University, Beijing 100871, China.
  • 6 GeneX Health Co. Ltd., Beijing 100195, China.
  • 7 Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Fudan University, Shanghai 200433, China.
  • 8 Center for Bioinformatics and Computational Biology, and the Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 9 Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China.
  • 10 Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • 11 Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • 12 Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • 13 Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • 14 WuXi Biologics (Shanghai) Co., Ltd., Shanghai City 201401, China.
  • 15 Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China. Electronic address: [email protected].
  • 16 Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Fudan University, Shanghai 200433, China. Electronic address: [email protected].
  • 17 Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China. Electronic address: [email protected].
PMID: 36943864 DOI: 10.1016/j.celrep.2023.112275
Abstract

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.

Keywords

CP: Cancer; brivanib; cGAS; chemosensitization; cyclic GMP-AMP synthase; platinum; type I IFN response.

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