Abstract 1417: Curtailing epithelial-mesenchymal plasticity for improved response to breast cancer therapy
Authors: Meisam Bagheri, Ian S. LaCroix, Xiaofeng Wang, Scott A. Gerber, Diwakar R. Pattabiraman
Journal: Cancer Research (2021)

Abstract Introduction: Two major hurdles faced in clinical cancer therapy are metastatic progression that results in the majority of cancer deaths, and resistance to therapy that fuels tumor relapse. The epithelial-mesenchymal transition (EMT) is a reversible cellular program that contributes to the intratumoral heterogeneity of carcinoma cells and confers traits that promote metastatic progression and resistance to chemotherapy. This proposal focuses on triple-negative breast cancer (TNBC), which accounts for 8-15% of all cases of breast cancer. The first-line choice for neoadjuvant chemotherapy is cyclophosphamide, followed by doxorubicin and paclitaxel in combination. In case of advanced/metastatic disease, third-line eribulin is administered as a single agent. In some cases of advanced disease, vinorelbine has also demonstrated efficacy. Eribulin, vinorelbine, and paclitaxel are microtubule poisons that act via mitotic blockade. Knowledge gap: Despite major advances in our understanding, the contributions of EMT research to improvements in cancer therapy have been minimal and yielded no clinically viable strategies to selectively modulate EMT in human tumors. Results:Our new data reveals that eribulin also utilizes a microtubule-independent mechanism to epigenetically induce MET. Using thermal proteome profiling and mass spectrometry analyses, we identify candidate target proteins of eribulin that enable it to act in an epigenetic fashion to induce MET.Eribulin is only able to induce MET in cells that received no prior chemotherapy; in cells pretreated with anthracyclines and taxanes, eribulin is unable to induce MET. Additionally, cells that were resistant to first-line taxane treatment were also resistant to eribulin-induced cell death. Using patient-derived xenograft (PDX) models, we have determined the optimal sequence of eribulin administration to maximize its MET-inducing and cytotoxic effects. Conclusions: We uncover that, working through altering the chromatin landscape and transcriptional profile of cells, eribulin induces MET and primes cells for subsequent chemotherapy. Additionally, the efficacy of eribulin is highest when administered in the treatment-naïve setting. By developing an understanding of eribulin's mechanism of action, treatment strategies can be optimized to maximize therapeutic potential by exploiting its effects in both mitotic blockade as well as MET. Upon completion of this study, we will better understand how MET-induced tumor differentiation would work and the impact that it would have on current conventional therapeutic strategies. Acknowledgements: Eribulin studies funded by Eisai Inc. Citation Format: Meisam Bagheri, Ian S. LaCroix, Xiaofeng Wang, Scott A. Gerber, Diwakar R. Pattabiraman. Curtailing epithelial-mesenchymal plasticity for improved response to breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1417.