Eribulin Synergistically Increases Anti-Tumor Activity of an mTOR Inhibitor by Inhibiting pAKT/pS6K/pS6 in Triple Negative Breast Cancer.

Abstract

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.

• Authors: 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
• Journal: Cells (Cells) Vol. 8 Issue 9 (08 30 2019) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 31480338 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Furans
• Ketones
• Protein Kinase Inhibitors
• Everolimus
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• eribulin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Carcinogenesis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Everolimus (pharmacology, therapeutic use)
• Female
• Furans (pharmacology, therapeutic use)
• Humans
• Ketones (pharmacology, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, SCID
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Triple Negative Breast Neoplasms (drug therapy)