Inhibition of Aurora kinase induces endogenous retroelements to induce a type I/III interferon response via RIG-I

Choy L. et al.

Type I interferon signaling is a crucial component of anti-viral immunity that has been linked to promoting the efficacy of some chemotherapeutic drugs. We developed a reporter system in HCT116 cells that detects activation of the endogenous IFI27 locus, an interferon (IFN) target gene. We screened a library of annotated compounds in these cells and discovered aurora kinase inhibitors (AURKi) as strong hits. Type I IFN signaling was found to be the most enriched gene signature after AURKi treatment in HCT116, and this signature was also strongly enriched in other colorectal cancer (CRC) cell lines. The ability of AURKi to activate IFN in HCT116 was dependent on MAVS and RIG-I, but independent of STING, whose signaling is deficient in these cells. MAVS dependence was recapitulated in other CRC lines with STING pathway deficiency, whereas in cells with intact STING signaling, the STING pathway was required for IFN induction by AURKi. AURKi's were found to induce expression of endogenous retroviruses (ERV's). These ERVs were distinct from those induced by the DNA methyltransferase inhibitors (DNMTi's), which can induce IFN signaling via ERV induction, suggesting a novel mechanism of action. The anti-tumor effect of alisertib in mice was accompanied by an induction of IFN expression in HCT116 or CT26 tumors. CT26 tumor growth inhibition by alisertib was absent in NOD/SCID mice vs. WT mice, and tumors from WT mice with alisertib treatment showed increased in CD8+ T cell infiltration, suggesting that anti-tumor efficacy of AURKi depends, at least in part, on an intact immune response.

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February, 2024


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