Eribulin mesylate: mechanism of action of a unique microtubule-targeting agent

Abstract

Eribulin mesylate (eribulin), an analogue of the marine natural product halichondrin B, is a microtubule-depolymerizing drug that has utility in the treatment of patients with breast cancer. Clinical trial results have demonstrated that eribulin treatment provides a survival advantage to patients with metastatic or locally advanced breast cancer previously treated with an anthracycline and a taxane. Furthermore, a pooled analysis of two pivotal phase III trials has demonstrated that eribulin also improves overall survival in several patient subgroups, including in women with HER2-negative disease and triple-negative breast cancer. This review covers the preclinical research that led to the clinical testing and approval of eribulin, as well as subsequent research that was prompted by distinct and unexpected effects of eribulin in the clinic. Initial studies with halichondrin B demonstrated unique effects on tubulin binding that resulted in distinct microtubule-dependent events and antitumor actions. Consistent with the actions of the natural product, eribulin has potent microtubule-depolymerizing activities and properties that distinguish it from other microtubule-targeting agents. Here, we review new results that further differentiate the effects of eribulin from other agents on peripheral nerves, angiogenesis, vascular remodeling, and epithelial-to-mesenchymal transition. Together, these data highlight the distinct properties of eribulin and begin to delineate the mechanisms behind the increased survival benefit provided by eribulin for patients.

Figure 1

Chemical structures of halichondrin B and eribulin.

Figure 2

Effect of MTDs of eribulin mesylate, paclitaxel and ixabepilone on sciatic nerve morphology. Tissue from mice treated with A, vehicle, B, eribulin, C, paclitaxel or D, ixabepilone. Severe pathological changes consistent with axonal degeneration of both large and small fibers are highlighted with red arrows and white arrowheads, respectively. No regeneration (e.g. thin myelinated fibers) was evident with paclitaxel or ixabepilone. Scale bar, 20 µm. MTD, maximum tolerated dose (23). (Reprinted from Wozniak K M, Nomoto K, Lapidus R G et al. Comparison of neuropathy-inducing effects of eribulin mesylate, paclitaxel, and ixabepilone in mice. Cancer Research 2011;71(11):3952–62. Reproduced with permission from AACR.).

Figure 3

Eribulin increases tumor vascular perfusion in an MX-1 rat xenograft model of human breast cancer. A. Representative DCE-MRI images of MX-1 tumors showing initial area under the curve (iAUC) maps prior to or on day 6 following eribulin treatment (0.1 or 0.3 mg/kg, days 0 and 4). A difference in perfusion between the tumor rim and tumor core is seen prior to treatment as indicated by lighter colors on the tumor rim and darker colors in the core. Changes in tumor perfusion after treatment are indicated by the change in color of the tumor core. B. Average volume transfer constant values (K^trans) in tumor rim or tumor core regions as determined by DC-MRI. *P < 0.05 versus vehicle. VEH, vehicle; ERI, eribulin; 0.1, 0.3, dose in mg/kg, every fourth day beginning in day 0; iAUC, initial area under the curve (36). (Reprinted from Funahashi Y, Okamoto K, Adachi Y et al. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Science 2014;105(10):1334–42. Copyright: The Authors. Reproduced with permission from John Wiley and Sons).

Figure 4

Eribulin reverses EMT in MX-1 human breast cancer xenografts in vivo. A, Schematic representation of treatment scheme. B, Representative immunohistochemistry images of human (i.e. tumor, not host) E-cadherin (upper), N-cadherin (middle) and ZEB-1 (lower) in tumor specimens from animals treated with eribulin 0.3, 1 and 3 mg/kg. Images taken at 100 × magnification. C, Quantification of immunohistochemistry staining of the markers shown in B. Data for individual tumors are presented as points, with mean ± standard error of the mean of the group shown by horizontal lines and error bars (n = 10). ***P < 0.001, ****P < 0.0001 versus control group (Dunnett-type multiple comparison test). EMT, epithelial-to-mesenchymal transition; IHC, immunohistochemistry; WB, Western blotting; ZEB-1, zinc finger E-box-binding homeobox 1 (39). (Reprinted from Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, et al. Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. British journal of cancer. 2014;110:1497-505. Reproduced with permission from Nature Publishing Group.