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

Sep 22, 2026

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Type I IFN signaling underpins antiviral immunity and is linked to improved responses to certain chemotherapeutic drugs. A reporter system in HCT116 cells was used to detect activation of the endogenous IFI􀀂􀀃 locus and to screen 1,443 annotated compounds, identifying Aurora kinase inhibitors (AURKi) as strong inducers. AURKi-triggered type I IFN signatures depended on MAVS and RIG-I, while being independent of deficient STING signaling in these cells. AURKi induced endogenous retrovirus expression distinct from DNA methyltransferase inhibitor (DNMTi) effects, and alisertib antitumor activity in mice coincided with IFN induction in tumors. Tumor control required intact immune responses, evidenced by loss of CT26 inhibition in immunodeficient NSG mice and increased CD8+ T-cell infiltration in wild-type animals.

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CategoryResearch & Report

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Reading Time40 min

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Abstract

Significance

Introduction

RESEARCH ARTICLE [https://doi.org/10.1158/2767-9764.CRC-23-0432](https://doi.org/10.1158/2767-9764.CRC-23-0432) Inhibition of Aurora Kinase Induces Endogenous Retroelements to Induce a Type I/III IFN Response via RIG-I Lisa Choy1 , Stephen Norris1 , Xiumin Wu1 , Ganesh Kolumam1 , Ari Firestone1 , Jeffrey Settleman1 , and David Stokoe1 OPEN ACCESS Check for updates ABSTRACT Type I IFN signaling is a crucial component of antiviral 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 IFI􀀂􀀃 locus, an 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 cell lines. The ability ofAURKi to activate IFN in HCT116 was dependent on MAVS and RIGI, but independent of STING, whose signaling is deficient in these cells. MAVS dependence was recapitulated in other colorectal cancer lines with STING pathway deficiency, whereas in cells with intact STING signaling, the STING pathway was required for IFN induction by AURKi. AURKis were found to induce expression of endogenous retroviruses (ERV) . These ERVs were distinct from those induced by the DNA methyltransferase inhibitors (DNMTi), which can induce IFN signaling via ERV induction, suggesting a novel mechanism of action. The antitumor effect of alisertibin mice was accompanied by an induction of IFN expression in HCT116 or CT26 tumors. CT26 tumor growth inhibition by alisertib was absent in NSG mice versus wildtype (WT) mice, and tumors from WT mice with alisertib treatment showed increased in CD8+ T-cell infiltration, suggesting that antitumor efficacy ofAURKi depends, at least in part, on an intact immune response. Significance: Some cancers deactivate STING signaling to avoid consequences of DNA damage from aberrant cell division. The surprising activation of MAVS/RIG-I signaling by AURKi might represent a vulnerability in STING signaling deficient cancers. Introduction IFNs are cytokine mediators of the innate antiviral immune response. Type I IFNs (most commonly α or β), can be produced by most cells in response to viral infection. Type III IFNs (λ IFNs), are produced by surface-exposed epithelial cells and engage distinct receptors. However, inducers, downstream signaling and target gene expression patterns of type I and type III IFNs are largely identical. Major inducers of IFN expression include the pattern recognition receptor pathways that recognize signatures of viral infection such as inappropriately modified or localized DNA (e.g., cGAS/STING) or RNA (e.g., RIG-I/MDA5/MAVS; ref. 1) . The role of IFNs is to orchestrate a suite of intracellular defenses against viral replication, increase class I MHC expression and 1 Calico Life Sciences LLC, South San Francisco, California. Current address for J. Settleman: Pﬁzer, La Jolla, California. Corresponding Author: David Stokoe, Calico Life Sciences, 1170 Veterans Boulevard, South San Francisco, CA 94080 . E-mail: [dhstokoe@calicolabs.com](dhstokoe@calicolabs.com) [doi:](doi: 10.1158/2767-9764.CRC-23-0432)[ 10.1158/2767-9764.CRC-23-0432](doi: 10.1158/2767-9764.CRC-23-0432) This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4 .0) license. © 2024 The Authors; Published by the American Association for Cancer Research antigen presentation, and stimulate production of cytokines such as CXCL10 that stimulate immune cell infiltration. While immune checkpoint blockade (ICB) agents, such as those targeting PDL1 or CTLA4 pathways, have demonstrated clinical efficacy in some cancers, current ICB treatments do not have activity in all cancers, sometimes due to an unfavorable

FAQs

How were Aurora kinase inhibitors identified as IFN inducers?

A reporter system in HCT116 cells detected activation of the endogenous IFI􀀂􀀃 locus after screening a library of 1,443 annotated compounds. Aurora kinase inhibitors (AURKi) emerged as strong hits.

Which signaling components are required for AURKi-induced IFN responses?

AURKi-induced activation in HCT116 depended on MAVS and RIG-I, while being independent of STING in cells where STING signaling is deficient.

What mechanism distinguishes AURKi effects from DNA methyltransferase inhibitors (DNMTi)?

AURKis induced endogenous retrovirus (ERV) expression, but these ERVs were distinct from those induced by DNMTi. This suggests a novel mechanism of action for AURKi-triggered IFN signaling.

Sep 22, 2026

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