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Abstract Microtubule-targeted agents (MTAs) are some of the most widely used and effective chemotherapeutics and they continue to find utility as the payloads of antibody-drug conjugates and in combination with targeted agents to improve response, including with immune checkpoint inhibitors. While all MTAs have shared antiproliferative effects, over the last decade it has become increasingly clear that individual drugs of this class have distinct effects on microtubule-dependent signaling and trafficking that are critical for their anticancer efficacy. We and others have demonstrated that eribulin is unique from other MTAs in its ability to promote vascular remodeling, reverse epithelial-to-mesenchymal transition (EMT), and increase immune infiltration into tumors both in animal models and in the clinic. However, the mechanism linking eribulin-mediated microtubule destabilization to these phenotypes, which are associated with improved overall survival of eribulin-treated patients, is unclear. We found that acute eribulin treatment at clinically relevant concentrations promotes the production of antitumor cytokines in both immune and cancer cells and synergizes with direct STING agonists to promote enhanced immune infiltration and improved antitumor efficacy in vivo in both breast and bladder cancer models. This effect was shown to involve activation of natural killer cells and is associated with TBK1-mediated IRF3 phosphorylation, which is regulated downstream of the microtubule associated GTPase GEF-H1. Intriguingly, GEF-H1 release from destabilized microtubules has also been shown to enhance the formation of focal adhesions and promote the differentiation of mesenchymal cells to a more epithelial phenotype. We show that eribulin is indeed sufficient to promote the formation and activation of focal adhesion complexes in mesenchymal triple-negative breast cancer cells, which was not observed when cells were subjected to treatment with microtubule stabilizing chemotherapeutics. Both genetic and pharmacological inhibitors of GEF-H1 were utilized to interrogate the relationship between eribulin-mediated microtubule destabilization and TBK1/IRF3-dependent immunological activation as well as the formation of RhoA-dependent focal adhesions and reversal of EMT-associated phenotypes. Together, our data provide a mechanistic rationale for unique effects of eribulin as compared to other classes of MTAs that could inform on the use of these widely used, but mechanistically underappreciated drugs in a more personalized manner and inform on their rational combination with targeted agents, including immunotherapy. Citation Format: Zaineb Hassouneh, Nancy Wilkinson, Leila Takahashi-Ruiz, Neelam Mukherjee, April L. Risinger. Mechanistic evaluations of the immunological and cell biological effects that distinguish eribulin from other microtubule-targeted chemotherapeutics abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5259.
Hassouneh et al. (Fri,) studied this question.