Eribulin Enhances Interferon Production by STING Agonists in Models of Triple‐Negative Breast Cancer

Abstract

Triple‐negative breast cancer (TNBC) is a highly heterogenous disease that lacks effective targeted treatment options. However, TNBC typically has a higher mutational burden and greater degree of immunogenicity than other breast tumors, making immunotherapy a viable strategy for effective treatment of this disease. Strategies to improve the response of TNBC patients to immune checkpoint inhibitors include the upregulation of the cGAS‐STING innate immune sensing pathway. Multiple STING agonists are in clinical development and have shown promise for the treatment of TNBC as single agents and combined with checkpoint inhibitors. We recently demonstrated that eribulin, a microtubule destabilizer used in the treatment of TNBC, functions as an indirect STING agonist because it promotes the release of mitochondrial DNA into the cytoplasm (Mol Pharmacol 100: 309‐318, 2021). We further hypothesized that eribulin could enhance the expression of type I interferons in combination with direct STING agonists. Indeed, our results show that the microtubule destabilizer eribulin significantly enhances interferon expression induced by STING agonists with diverse mechanisms of action in human monocytes and TNBC cells. This phenotype is shared with other microtubule destabilizers, including vinorelbine, but not with the microtubule stabilizing agent paclitaxel, which is also used in the treatment of TNBC. The eribulin‐mediated enhancement of interferon expression induced by multiple pharmacological STING agonists, as well as HT‐DNA and cGAMP ligands, occurs within 6 hours and is mechanistically distinct from the previously reported eribulin‐mediated release of mitochondrial DNA into the cytoplasm. This response is dependent on TBK1 and associated with TBK1 phosphorylation but was not inhibited by the STING antagonist H‐151 or by inhibition of the JNK or JAK1/2 signaling pathways in TNBC cells. Ongoing in vivo studies are determining the effects of eribulin on the immunological response to TNBC tumors alone and in combination with pharmacological STING agonists and whether this improves antitumor efficacy. These studies will determine if eribulin, a chemotherapeutic agent already used in the treatment of TNBC, can increase the immunogenicity of TNBC tumors and inform on combination treatment of eribulin with STING agonists and potentially other immunotherapies.