Fostamatinib (R788), a spleen tyrosine kinase inhibitor, sensitizes pancreatic cancer cells to oncolytic vesicular stomatitis virus

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with limited treatment options. Oncolytic virus (OV) therapy exploits replication-competent viruses, including vesicular stomatitis virus (VSV), to preferentially infect and kill malignant cells, while sparing non-malignant cells. We previously showed that human PDAC cell lines are highly heterogeneous in their permissiveness to VSV and other OVs. Although ruxolitinib and other JAK1/2 inhibitors can enhance VSV replication in resistant PDAC cell lines, they also increase the susceptibility of non-malignant cells to OVs. Here, we show that fostamatinib (R788), a spleen tyrosine kinase (SYK) inhibitor approved by the Food and Drug Administration (FDA) for the treatment of chronic immune thrombocytopenia (ITP), specifically boosts VSV replication in PDAC cells without affecting non-malignant cells. Fostamatinib treatment suppressed both the secretion of interferons and inflammatory cytokines by VSV-infected PDAC cells and diminished their responsiveness to type I interferons. However, unlike ruxolitinib, fostamatinib promoted viral replication without severely impeding innate immune responses essential for adaptive anti-cancer immunity. Additionally, fostamatinib inhibited PDAC cell proliferation even in the absence of viral infection, while ruxolitinib did not. Our data suggest that fostamatinib may be repurposed as an effective drug that enhances OV therapy in PDAC by promoting OV replication and suppressing tumor growth.