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

by Selleckchem | Sep 16 2023

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.

Comments:

The passage you provided describes a study that investigated the immunological effects of the microtubule destabilizer drug eribulin in the treatment of triple-negative breast cancer (TNBC). The researchers found that eribulin, in combination with STING agonists (which activate the STING pathway involved in innate immune sensing), enhanced the expression of interferon beta (IFNβ), an immunogenic cytokine, in immune cells and TNBC models.

The study compared eribulin with other microtubule-targeted drugs like taxanes and found that while they all have antimitotic effects, eribulin had a unique ability to enhance IFNβ expression when combined with STING agonists. This synergistic effect was particularly pronounced when eribulin was combined with ADU-S100 and E7766, two STING agonists that were undergoing clinical trials at the time of the study.

The researchers investigated the mechanism behind eribulin's enhancement of STING signaling and found that it was downstream of microtubule disruption but independent of the release of mitochondrial DNA, which is a known trigger for innate immune responses. Eribulin did not interfere with the requirement of ER exit for STING activation nor inhibit STING degradation. However, it significantly enhanced the phosphorylation of IRF3, a transcription factor involved in the RNA sensing pathway that leads to IFNβ production.

Furthermore, the study showed that eribulin, when combined with a STING agonist or tumor, increased the population of activated CD4+ T-cells in vivo, indicating its potential as an immune adjuvant. The researchers also tested the combination of eribulin with ADU-S100 in a murine mammary tumor model and observed significant antitumor efficacy.

Overall, the findings suggest that microtubule-targeted chemotherapeutics, such as eribulin, can have distinct immunological effects. Eribulin's ability to enhance innate immune sensing pathways, particularly in combination with STING agonists, supports its potential use in combination with immunotherapies for more effective treatment of TNBC and other types of cancer.