The Microtubule Destabilizer Eribulin Synergizes with STING Agonists to Promote Antitumor Efficacy in Triple-Negative Breast Cancer Models

SIMPLE SUMMARY: Microtubule-targeting agents are a class of chemotherapeutics used to treat triple-negative breast cancer (TNBC). These include drugs such as eribulin that depolymerize microtubules, as well as microtubule stabilizing taxanes such as paclitaxel. TNBC is a relatively immunogenic form of breast cancer and one strategy to further increase immunogenicity is through activation of the cGAS-STING innate immune sensing pathway. We demonstrate that eribulin enhances interferon production in combination with STING agonists undergoing clinical development in immune and TNBC cells. This phenotype is shared with other microtubule destabilizers, but not with stabilizers, suggesting a mechanism downstream of microtubule depolymerization. We determined that eribulin also enhanced immunogenic responses in vivo and improved antitumor efficacy in a spontaneous murine mammary tumor model when combined with a STING agonist. These findings highlight important mechanistic distinctions between microtubule targeted chemotherapeutic drugs and provide an opportunity to improve the efficacy of immunotherapies using a compound currently used in TNBC. ABSTRACT: Eribulin is a microtubule destabilizer used in the treatment of triple-negative breast cancer (TNBC). Eribulin and other microtubule targeted drugs, such as the taxanes, have shared antimitotic effects, but differ in their mechanism of microtubule disruption, leading to diverse effects on cellular signaling and trafficking. Herein, we demonstrate that eribulin is unique from paclitaxel in its ability to enhance expression of the immunogenic cytokine interferon beta (IFNβ) in combination with STING agonists in both immune cells and TNBC models, including profound synergism with ADU-S100 and E7766, which are currently undergoing clinical trials. The mechanism by which eribulin enhances STING signaling is downstream of microtubule disruption and independent of the eribulin-dependent release of mitochondrial DNA. Eribulin did not override the requirement of ER exit for STING activation and did not inhibit subsequent STING degradation; however, eribulin significantly enhanced IRF3 phosphorylation and IFNβ production downstream of the RNA sensing pathway that converges on this transcription factor. Additionally, we found that eribulin enhanced the population of activated CD4(+) T-cells in vivo when combined with either a STING agonist or tumor, demonstrating the ability to function as an immune adjuvant. We further interrogated the combination of eribulin with ADU-S100 in the MMTV-PyVT spontaneous murine mammary tumor model where we observed significant antitumor efficacy with combination treatment. Together, our findings demonstrate that microtubule targeted chemotherapeutics have distinct immunological effects and that eribulin’s ability to enhance innate immune sensing pathways supports its use in combination with immunotherapies, such as STING agonists, for the more effective treatment of TNBC and other malignancies.