Small Molecule Compound Sensitizes Chemotherapy By Targeting CGAS To Boost Antitumor Immunity

Background: Platinum-based chemotherapy is one of the most effective treatment for patients with lung cancer.However,chemotherapy failure or inadequate response challenges the clinical application of platinum-based cancer chemotherapeutics.Platinum is passively transported into tumor cells.Subsequently,it targets and combines with the DNA bases,and changes the structure of DNA to form the DNA adducts such as platinum-monoadducts,intrastand crosslinks and interstand crosslinks,thereby inhibiting DNA replication and transcription,inducing cell apoptosis.Cyclic guanosine monophosphate adenosine monophosphate synthase(cGAS)is an important recognition receptor for innate immune responses and a cytoplasmic DNA sensor,which thereby catalyzes the formation of second messenger CyclicGMP-AMP(cGAMP).cGAMP then binds to the adaptor stimulator of interferon genes(STING)and leads to the activation of the transcription factors NF-κB and IFN regulatory factor 3(IRF3)as well as to the production of various cytokines including type I IFNs.In this way,cGAS–STING signaling bridges the DNA damaging capacity of chemotherapeutic agents with the activation of antitumor immune responses.Inspiringly,the combination of IFN improves the efficacy of platinum-based chemotherapy on tumors in preclinical and clinical research.Therefore,the identification of cGAS agonists would be helpful in cancer treatment by leveraging on cGAS-mediated antitumor immunity in response to DNA damage caused by chemotherapy in patients.Methods and Results: Here,by using the oblique-incidence reflectivity difference(OI-RD)and high throughput small-molecule-microarray-based screening of cGAS interacting compounds,we identified brivanib,known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor,as a novel cGAS agonist in vitro.Brivanib markedly enhanced platinum-induced STING-TBK1-type I IFN response in tumor cells through cGAS.Importantly,brivanib synergized with cisplatin in restricting the growth of xenografted Lewis Lung Cancer(LLC)cells by boosting CD8+ T cell response in a cGAS-dependent manner.We further verified the synergistic anti-tumor efficacy of the brivanib and cisplation with patient-derived tumor-like cell clusters(PTCs).PTCs result from the self-assembly and proliferation of primary epithelial,fibroblast,and immune cells,which structurally and functionally recapitulate original tumors.Drug efficacy assay demonstrated that brivanib markedly synergized with cisplatin in restricting tumor growth in PTCs when cGAS expression was high,but not when cGAS expression was low or not detectalbe,indicating that the presence of cGAS may be critical for the synergy of brivanib and cisplatin in cancer therapy.Mechanistically,brivanib enhanced the DNA binding affinity of cGAS by targeting leucine 495 of cGAS.Moreover,leucine 495 of cGAS was essential for brivanib-mediated promoting effect on cisplatin-mediated type I IFN response and inhibition of tumor growth.Clinically,higher expression of cGAS in tumor renders a more favorable response to platinum-based chemotherapeutic regimens and better prognosis in lung cancer patient.Conclusions: Taken together,our findings discover cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.This study identifies the first cGAS agonist activator and provides new strategy for improving chemosensitization by targeting cGAS to enhance antitumor immunity.