| First Author | Liu H | Year | 2023 |
| Journal | Cell Rep | Volume | 42 |
| Issue | 3 | Pages | 112275 |
| PubMed ID | 36943864 | Mgi Jnum | J:354630 |
| Mgi Id | MGI:7463822 | Doi | 10.1016/j.celrep.2023.112275 |
| Citation | Liu H, et al. (2023) Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity. Cell Rep 42(3):112275 |
| abstractText | 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. |
