Eribulin Synergistically Increases Anti-Tumor Activity of an mTOR Inhibitor by Inhibiting pAKT/pS6K/pS6 in Triple Negative Breast Cancer
Wei Wen,
Emily Marcinkowski,
David Luyimbazi,
Thehang Luu,
Quanhua Xing,
Jin Yan,
Yujun Wang,
Jun Wu,
Yuming Guo,
Dylan Tully,
Ernest S. Han,
Susan E. Yost,
Yuan Yuan,
John H. Yim
Affiliations
Wei Wen
Division of Surgery, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
Emily Marcinkowski
Division of Surgery, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
David Luyimbazi
Division of Surgery, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
Thehang Luu
Department of Medical Oncology and Molecular Therapy, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
Quanhua Xing
Division of Surgery, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
Jin Yan
Division of Surgery, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
Yujun Wang
Division of Surgery, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
Jun Wu
Department of Comparative Medicine, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
Yuming Guo
Department of Comparative Medicine, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
Dylan Tully
Division of Surgery, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
Ernest S. Han
Division of Surgery, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
Susan E. Yost
Department of Medical Oncology and Molecular Therapy, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
Yuan Yuan
Department of Medical Oncology and Molecular Therapy, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
John H. Yim
Division of Surgery, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Rd., Duarte, CA 91010, USA
Unlike other breast cancer subtypes, patients with triple negative breast cancer (TNBC) have poor outcomes and no effective targeted therapies, leaving an unmet need for therapeutic targets. Efforts to profile these tumors have revealed the PI3K/AKT/mTOR pathway as a potential target. Activation of this pathway also contributes to resistance to anti-cancer agents, including microtubule-targeting agents. Eribulin is one such microtubule-targeting agent that is beneficial in treating taxane and anthracycline refractory breast cancer. In this study, we compared the effect of eribulin on the PI3K/AKT/mTOR pathway with other microtubule-targeting agents in TNBC. We found that the phosphorylation of AKT was suppressed by eribulin, a microtubule depolymerizing agent, but activated by paclitaxel, a microtubule stabilizing agent. The combination of eribulin and everolimus, an mTOR inhibitor, resulted in an increased reduction of p-S6K1 and p-S6, a synergistic inhibition of cell survival in vitro, and an enhanced suppression of tumor growth in two orthotopic mouse models. These findings provide a preclinical foundation for targeting both the microtubule cytoskeleton and the PI3K/AKT/mTOR pathway in the treatment of refractory TNBC.
