Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity

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

doi:10.1016/j.celrep.2023.112275

Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity

Cell Rep. 2023 Mar 28;42(3):112275. doi: 10.1016/j.celrep.2023.112275. Epub 2023 Mar 20.

Authors

Haipeng Liu¹, Hang Su², Fei Wang³, Yifang Dang⁴, Yijiu Ren², Shenyi Yin⁵, Huinan Lu⁶, Hang Zhang⁷, Jun Wu⁸, Zhu Xu⁹, Mengge Zheng¹⁰, Jiani Gao², Yajuan Cao¹⁰, Junfang Xu¹⁰, Li Chen¹⁰, Xiangyang Wu¹¹, Mingtong Ma³, Long Xu², Fang Wang², Jianxia Chen¹¹, Chunxia Su¹², Chunyan Wu¹³, Huikang Xie¹³, Jijie Gu¹⁴, Jianzhong Jeff Xi⁵, Baoxue Ge¹⁵, Yiyan Fei¹⁶, Chang Chen¹⁷

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: haipengliu@tongji.edu.cn.
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: baoxue_ge@tongji.edu.cn.
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: fyy@fudan.edu.cn.
¹⁷ Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China. Electronic address: changchenc@tongji.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alanine* / analogs & derivatives
Antineoplastic Agents* / administration & dosage
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
Cisplatin / administration & dosage
High-Throughput Screening Assays
Humans
Interferons / immunology
Neoplasms* / drug therapy
Nucleotidyltransferases* / metabolism
Triazines*
Tumor Cells, Cultured / drug effects

Substances

brivanib
Triazines
Alanine
cGAS protein, human
Nucleotidyltransferases
Interferons
Cisplatin
Antineoplastic Agents