Abstract 1785: Eribulin alters the chromatin landscape to induce MET, attenuating metastatic progression sensitizing breast tumors to subsequent chemotherapy
Authors: Bagheri Meisam , Ognjenovic Nevena B. , Mohamed Gadisti Aisha , LaCroix Ian S. , McCray Andrew , Muller Kristen E. , Wang Xiaofeng , Gerber Scott A. , Pattabiraman Diwakar R. 
Published: June 2022

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. The standard of care for triple negative breast cancer (TNBC) remains neoadjuvant chemotherapy where cyclophosphamide, doxorubicin and paclitaxel are administered 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 inhibitors 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, in addition to blocking tubulin polymerization, utilizes epigenetic mechanisms to induce MET. Using thermal proteome profiling and mass spectrometry analyses, we identify candidate target proteins of eribulin that could enable it to act in an epigenetic fashion to induce MET.Treating TNBC patient-derived xenograft tumors with eribulin induces a significant reduction in metastatic burden, with the remaining metastatic colonies exhibiting a well-differentiated histopathology. Eribulin efficiently induce MET in cells that have received no prior chemotherapy; in cells pretreated with anthracyclines and taxanes, eribulin is less efficient at MET induction. 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 activity 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, Nevena B. Ognjenovic, Gadisti Aisha Mohamed, Ian S. LaCroix, Andrew McCray, Kristen E. Muller, Xiaofeng Wang, Scott A. Gerber, Diwakar R. Pattabiraman. Eribulin alters the chromatin landscape to induce MET, attenuating metastatic progression sensitizing breast tumors to subsequent chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1785.