Abstract 4910: Eribulin rapidly impairs TGF-β signaling

Abstract

Abstract Microtubule targeting agents (MTAs) continue to be valuable in treating breast cancer. While decades of research have shown that these drugs cause mitotic arrest in cells by suppressing the dynamic instability of microtubules, recent evidence demonstrates that the ability of MTAs to disrupt the microtubule-dependent transport of key signaling components in interphase cells likely contributes to their anticancer actions. Cell signaling messages are relayed by proteins that organize or scaffold signaling hubs. These signaling nodes facilitate the complex organization and coordination of multiple signaling partners. NEDD9 is a member of the CAS scaffold family and it has been shown to coordinate TGF-β signaling, a driver of oncogenesis and epithelial-to-mesenchymal transition (EMT). Ligand-mediated stimulation of TGF-β receptors leads to the activation of downstream canonical and non-canonical signaling pathways. These pathways collectively induce the expression of Snail and Slug, key transcriptional-repressors that promote EMT. We tested the hypothesis that a short-term treatment of breast cancer cells with eribulin or 3 other clinically relevant MTAs would differentially disrupt interphase microtubules and alter TGF-β-dependent signaling. BT-549 cells were treated for 2 h with concentrations of MTAs that are clinically relevant and cause maximum disruption of the interphase microtubule network; 100 nM was used for the destabilizers, eribulin and vinorelbine and 1 µM was used for the stabilizers, paclitaxel and ixabepilone. The results showed that eribulin and vinorelbine significantly inhibited TGF-β- induced expression of Snail and Slug. The microtubule stabilizers had no effect on Snail and Slug expression following TGF-β stimulation. Further studies evaluated whether NEDD9 contributes to the downregulation of Snail and Slug. Co-immunoprecipitation and knockdown studies suggest that eribulin impairs the ability of NEDD9 to scaffold TGF-β signaling partners, thus inhibiting downstream transcriptional signaling. Consistent with the ability of eribulin to reverse EMT in experimental models within 7 days, this study begins to shed light on the mechanisms underlying its action. Funding for this work was provided by Eisai Inc. Citation Format: Roma Kaul, April L. Risinger, Susan L. Mooberry. Eribulin rapidly impairs TGF-β signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4910. doi:10.1158/1538-7445.AM2017-4910