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We have developed a novel chemotherapeutic strategy targeting Tpm3.1, a tropomyosin isoform that is a core component of the actin cytoskeleton in cancer cells1. The lead compound, TR100, and the preclinical lead ATM3507, prevent Tpm3.1 from stabilizing actin filaments, leading to the collapse of the actin cytoskeleton in cancer cells, and has shown promise in preclinical trials1. Both compounds strongly synergize with the anti-microtubule drug vincristine (VCR) in multiple tumor types in vitro and in vivo2. Further studies in HeLa cells reveal that low doses of TR100 do not impact cell cycle progression, but sensitize the cells to VCR-induced mitotic arrest. Treatment with this drug combination promotes multipolar spindle formation and multipolar division, as well as increased apoptosis. Given that Tpm3.1 is enriched at the cell cortex during metaphase, we hypothesized that the interaction of astral microtubules with cortical actin structures is mediated in part by Tpm3.1, and disruption of this association leads to observed spindle defects. This hypothesis is supported by our data showing that Tpm3.1 interacts with EB1 and dynein, which play prominent roles in regulating microtubule activity. 1. Stehn JR, et al. Cancer Res. 2013; 73: 5169-5182. 2. Currier MA, et al. Mol. Cancer Ther. 2017; 16: 1555-1565