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
  • 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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