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.
Highlights
Triple negative breast cancer (TNBC) accounts for 12–17% of all breast cancers, and is characterized by a poor overall and relapse-free survival [1]
We investigated the effect of eribulin and a mTOR inhibitor, either alone or in combination, on the PI3K/AKT/mTOR
Our study demonstrates that the combination of eribulin plus everolimus markedly enhances the suppression of tumors compared to treatment with eribulin or everolimus alone in two mouse models of triple negative breast cancer (TNBC): a syngeneic model with a well-known highly metastatic TNBC (4T1) and a xenogeneic model with human TNBC (MDA-MB-468)
Summary
Triple negative breast cancer (TNBC) accounts for 12–17% of all breast cancers, and is characterized by a poor overall and relapse-free survival [1]. The PI3K/AKT/mTOR pathway is a key signal transduction pathway that mediates cellular responses to growth factors [7,8,9]. This pathway affects many cellular functions, including cell survival, cell proliferation, and apoptosis [10]. Patients with TNBC often have high levels of AKT expression and activation of the PI3K/AKT/mTOR pathway [2,4,11,12]. Treatment targeting the PI3K/AKT/mTOR pathway in patients with alterations in the PI3K/AKT/mTOR pathway resulted in significantly better outcomes in both treatment naïve and previously treated patients [2,12]. An mTOR inhibitor, when used alone, can induce increased levels of p-AKT via a negative feedback loop, leading to
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