Abstract 1785: Eribulin alters the chromatin landscape to induce MET, attenuating metastatic progression sensitizing breast tumors to subsequent chemotherapy

• Published in: Cancer research (Chicago, Ill.) Ill.), 2022-06, Vol.82 (12_Supplement), p.1785-1785
• Main 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.
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2022-1785

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 maximiz