Inhibition of Aurora Kinase Induces Endogenous Retroelements to Induce a Type I/III IFN Response via RIG-I

• DOI: 10.1158/2767-9764.crc-23-0432
• Publication Date: 2024-02-15T15:12:45Z
• Authors: Lisa Choy; Stephen Norris; Xiumin Wu; Ganesh Kolumam; Ari Firestone; Jeffrey Settleman; David Stokoe
• Keywords: RIG-I

Type I IFN signaling is a crucial component of antiviral immunity that has been linked to promoting the efficacy some chemotherapeutic drugs. We developed reporter system in HCT116 cells detects activation endogenous IFI27 locus, an target gene. screened library annotated compounds these and discovered Aurora kinase inhibitors (AURKi) as strong hits. was found be most enriched gene signature after AURKi treatment HCT116, this also strongly other colorectal cancer cell lines. The ability activate dependent on MAVS RIG-I, but independent STING, whose deficient cells. dependence recapitulated lines with STING pathway deficiency, whereas intact signaling, required for induction by AURKi. AURKis were induce expression retroviruses (ERV). These ERVs distinct from those induced DNA methyltransferase (DNMTi), which can via ERV induction, suggesting novel mechanism action. antitumor effect alisertib mice accompanied or CT26 tumors. tumor growth inhibition absent NSG versus wildtype (WT) mice, tumors WT showed increased CD8+ T-cell infiltration, depends, at least part, immune response.