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

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Type I interferon (IFN) signaling is vital for antiviral immunity and can enhance chemotherapy efficacy.
• Colorectal cancer cells often exhibit deficiencies in STING signaling.
• Aurora kinase inhibitors (AURKi) are investigated for their therapeutic potential in cancer treatment.

Purpose of the Study:

• To identify novel therapeutic strategies for colorectal cancer by screening compounds for their ability to activate IFN signaling.
• To elucidate the mechanism by which AURKi activate IFN signaling and its dependence on specific pathways.
• To evaluate the in vivo efficacy of AURKi and its relationship with the immune response.

Main Methods:

• Development of a reporter system in HCT116 cells to detect IFI27 locus activation.
• Screening of an annotated compound library to identify hits.
• Gene signature enrichment analysis and pathway dependency studies (MAVS, RIG-I, STING).
• Analysis of endogenous retrovirus (ERV) induction.
• In vivo studies using mouse models (NSG and WT mice) to assess tumor growth inhibition and immune cell infiltration.

Main Results:

• AURKi were identified as potent activators of Type I IFN signaling in HCT116 cells.
• IFN activation by AURKi in STING-deficient cells was dependent on MAVS and RIG-I signaling.
• AURKi induced expression of endogenous retroviruses (ERVs) through a novel mechanism distinct from DNMT inhibitors.
• In vivo, alisertib (an AURKi) demonstrated antitumor effects accompanied by IFN induction and increased CD8+ T-cell infiltration in tumors.
• Antitumor efficacy of alisertib was dependent on an intact immune response.

Conclusions:

• AURKi represent a novel class of compounds that activate Type I IFN signaling, potentially through ERV induction.
• The MAVS/RIG-I pathway activation by AURKi offers a therapeutic vulnerability in STING-deficient cancers.
• AURKi's antitumor efficacy is at least partially mediated by the induction of an anti-tumor immune response.