Abstract 6430: Redefining therapy regimens for triple negative breast cancer - Exploiting the epigenetic effects of eribulin action
Authors: Bagheri Meisam , Mohamed Aisha , Ognjenovic Nevena B. , Pattabiraman Diwakar R. 
Published: September 2020

Abstract
While the advent of targeted therapy has led to vast improvements in outcomes for certain types of breast cancer, the standard of care for triple negative breast cancer (TNBC) still remains chemotherapy. A major clinical hurdle in the successful management of this disease is the eventual development of therapeutic resistance and disease relapse in more aggressive forms. Our research centers on the improving therapeutic outcomes for TNBC through the induction of tumor differentiation. Current therapy regimens for TNBC involve the administration of anthracyclines such as doxorubicin, and taxanes such as paclitaxel, typically in combination. When patients present with advanced or metastatic disease, or upon relapse following treatment with an anthracycline or a taxane, eribulin is administered as third-line therapy. We observe that treatment of TNBC cell lines such as SUM159, BT549 or Hs578T, or mouse models such as MMTV-PyMT or C3(1)-Tag with either doxorubicin, paclitaxel or eribulin results in the emergence of resistant subpopulations of cells. In the case of doxorubicin and paclitaxel, the resistant clones exhibit mesenchymal properties due to therapy-induced epithelial-to-mesenchymal transition (EMT). In the case of eribulin, however, these resistant subpopulations are epithelial in nature, having undergone mesenchymal-to-epithelial transition (MET). Our work sheds like on the epigenetic mechanisms that drive eribulin-induced changes to cell state, providing insights into its non-antimitotic actions. Assaying the chromatin landscape of eribulin-resistant vs. paclitaxel-resistant cells by ATAC-Seq reveals genome-wide repression of transcription upon treatment with eribulin. This is accompanied by a severe loss in H3K4me3 that suppresses the transcription of thousands of promoter regions. By carrying out thermal proteome profiling, we identify targets of eribulin that could be responsible for its effects in epigenomic reprogramming and induction of differentiation. Surprisingly, doxorubicin- or paclitaxel-resistant cells are no longer susceptible to subsequent treatment with eribulin, do not undergo MET, and remain difficult to eliminate. Eribulin-resistant cells, however, owing to their epithelial phenotype, are eliminated by subsequent treatment with other drugs including doxorubicin and paclitaxel. Current treatment regimens in the clinic administer eribulin only to patients that have previously received anthracyclines and/or taxanes, never in the treatment-naive or neoadjuvant setting. Our findings highlight the importance of designing treatment regimens based on a clear understanding of the effects of individual drugs on cellular phenotype, including altered responsiveness induced by prior lines of therapy. Our work has major implications for the clinical use and the sequence of administration of chemotherapy with the potential to rapidly alter the course of tumor progression in TNBC by altering treatment regimens.
Citation Format: Meisam Bagheri, Aisha Mohamed, Nevena B. Ognjenovic, Diwakar R. Pattabiraman. Redefining therapy regimens for triple negative breast cancer - Exploiting the epigenetic effects of eribulin action [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6430.