@article {FermainttMOLPHARM-AR-2021-000297, author = {Charles S. Fermaintt and Leila Takahashi-Ruiz and Huiyun Liang and Susan L. Mooberry and April L. Risinger}, title = {Eribulin activates the cGAS-STING pathway via the cytoplasmic accumulation of mtDNA}, elocation-id = {MOLPHARM-AR-2021-000297}, year = {2021}, doi = {10.1124/molpharm.121.000297}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Microtubule targeting agents (MTAs), including both microtubule stabilizers and destabilizers, are highly effective chemotherapeutic drugs used in the treatment of solid tumors and hematological malignancies. In addition to the shared ability of all MTAs to block cell cycle progression, growing evidence shows that different agents of this class can also have mechanistically distinct effects on non-mitotic microtubule-dependent cellular processes, including cellular signaling and transport. Herein, we test the biological hypothesis that MTAs used in the treatment of triple-negative breast cancer (TNBC) can differentially affect innate immune signaling pathways independent of their antimitotic effects. Our data demonstrate that the microtubule destabilizer eribulin, but not the microtubule stabilizer paclitaxel, induces cGAS-STING-dependent expression of interferon β in both myeloid and TNBC cells. Activation of the cGAS-STING pathway by eribulin was further found to be mediated by the accumulation of cytoplasmic mitochondrial DNA. Together, these findings provide mechanistic insight into how eribulin can induce innate immune signaling independent of its antimitotic or cytotoxic effects. Significance StatementMicrotubule targeted agents are often used in the treatment of breast cancer and, most recently, have been used in combination with immune checkpoint inhibitors to improve their efficacy. While all clinically approved MTAs share an antimitotic mechanism of action, their distinct effects on interphase microtubules can promote differential downstream signaling consequences. We show that the microtubule destabilizer eribulin, but not the microtubule stabilizer paclitaxel, activates the cGAS-STING innate immune signaling pathway through the accumulation of mitochondrial DNA in the cytoplasm.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2021/07/25/molpharm.121.000297}, eprint = {https://molpharm.aspetjournals.org/content/early/2021/07/25/molpharm.121.000297.full.pdf}, journal = {Molecular Pharmacology} }