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VEGF receptor inhibitor brivanib sensitizes chemotherapy by targeting cGAS to boost antitumor immunity

ABSTRACT: Chemoresistance challenges the clinical application of most widely used platinum-based cancer chemotherapeutics which canonically function through inducing DNA damage. The DNA sensor cyclic GMP–AMP synthase (cGAS) connects genome instability to type I IFN response which confers vulnerability to platinum treatment. Here, by using a high throughput small-molecule-microarray-based screening of cGAS interacting compounds, we identified brivanib, known as an inhibitor of the vascular endothelial growth factor receptor (VEGFR), as a novel cGAS agonist. Brivanib markedly enhanced platinum-induced STING-TBK1-type I IFN response in tumor cells indispensable of cGAS. Importantly, brivanib synergizes the effect of cisplatin in restricting the growth of xenografted Lewis Lung Cancer (LLC) cells by boosting CD8+ T cell response in a cGAS-dependent manner. Mechanistically, brivanib enhances the DNA binding affinity of cGAS by directly targeting leucine 495 of cGAS. Moreover, leucine 495 of cGAS is 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. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE190016 | GEO | 2022/12/31

REPOSITORIES: GEO

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