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

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.

Eribulin induces micronuclei and enhances the nuclear localization of cGAS in triple-negative breast cancer cells

“…The mechanistic basis for this synergy involves the cGAS protein's affinity for DNA termini, thereby impeding the access of critical DNA repair machinery components, including the MRN complex (comprising MRE11, RAD50, and NBS1) and 53BP1—both vital for the initial phases of DNA repair processes like homologous recombination (HR) and non-homologous end joining (NHEJ) 18 . Consistent with prior findings, our data indicate that ERI preferentially activates the cGAS-STING pathway compared to PTX, reinforcing the notion that a combined ERI and STING agonist therapy could be a viable oncological strategy 36 , 37 .…”

“…In vivo studies have demonstrated the potential therapeutic efficacy of combining ERI with STING agonists 36 . The mechanistic basis for this synergy involves the cGAS protein's affinity for DNA termini, thereby impeding the access of critical DNA repair machinery components, including the MRN complex (comprising MRE11, RAD50, and NBS1) and 53BP1—both vital for the initial phases of DNA repair processes like homologous recombination (HR) and non-homologous end joining (NHEJ) 18 .…”

Vinorelbine causes a neuropathic pain-like state in mice via STING and MNK1 signaling associated with type I interferon induction

“…Some studies have suggested that the STING pathway is activated by mitochondrial or nuclear DNA release induced by cellular damage resulting from the treatment with MTAs, but it has also been proposed that STING activation occurs downstream of the microtubule disruption triggered by these chemotherapeutics. 12 , 54 , 72 Whatever the precise mechanism turns out to be, the discovery that vinorelbine-induced pain depends on STING-type I IFN signaling makes it possible to implement strategies to alleviate the neuropathic pain state caused by the chemotherapeutic. We demonstrate that this can be achieved by targeting MNK1-eIF4E signaling.…”

Proteomic analysis of holocarboxylase synthetase deficient-MDA-MB-231 breast cancer cells revealed the biochemical changes associated with cell death, impaired growth signaling, and metabolism

“…STING1, an ER-bound protein, is crucial for autophagy and programmed cell death (Zhang et al, 2021a). A recent study shows that Eribulin, an anti-cancer drug used to treat breast cancer and liposarcoma, triggers cancer cell death via the STING1-dependent signaling axis (Fermaintt et al, 2021;Takahashi-Ruiz et al, 2022), indicating its role as a cell-death-promoting factor. Upregulation of these proapoptotic proteins may be induced in response to HLCS suppression.…”