What is the mechanism of action of Eribulin (Halaven)?

Eribulin Mechanism of Action

Eribulin is a nontaxane microtubule inhibitor that works by binding to a distinct site on β-tubulin, leading to inhibition of microtubule dynamics, G2/M phase cell-cycle arrest, and ultimately apoptosis. 1

Primary Mechanism: Microtubule Disruption

• Eribulin binds to a unique site on β-tubulin that is distinct from other microtubule-targeting agents like taxanes, resulting in a different mechanism of microtubule inhibition 2
• This binding inhibits microtubule dynamics rather than stabilizing or destabilizing microtubules like traditional agents 1
• The disruption of microtubule function leads to prolonged mitotic blockage, causing cells to arrest in the G2/M phase of the cell cycle 2, 3
• After prolonged mitotic arrest, cells undergo apoptosis (programmed cell death) 2, 3

Distinguishing Features from Other Microtubule Agents

• Eribulin is classified as a nontaxane microtubule inhibitor, differentiating it from taxanes (paclitaxel, docetaxel) and vinca alkaloids 1
• The distinct binding site on β-tubulin allows eribulin to maintain activity in tumors that may be resistant to taxanes 2
• Unlike taxanes that stabilize microtubules, eribulin's mechanism involves interference with microtubular growth through a unique pathway 3

Additional Non-Mitotic Effects

• Beyond its mitotic effects, eribulin exhibits effects on epithelial-mesenchymal transition (EMT), potentially reversing this process that contributes to metastasis 4, 5
• Eribulin has demonstrated effects on tumor vasculature and vascular remodeling, which may contribute to its anticancer activity 4, 5
• These vascular and microenvironment modifications represent nonmitotic mechanisms that distinguish eribulin from traditional cytotoxic agents 4

Clinical Implications of Mechanism

• The unique mechanism allows eribulin to be effective in heavily pretreated patients whose cancers have progressed after anthracyclines and taxanes 1
• Activity has been demonstrated in leiomyosarcoma and adipocytic sarcomas (32% and 42% progression-free survival at 12 weeks, respectively) 1
• In metastatic breast cancer, eribulin showed improved overall survival (median 13.1 months vs 10.6 months with physician's choice) with a 19% risk reduction (HR 0.81, P=0.041) 1

Chemical Origin

• Eribulin is a synthetic analog of halichondrin B, a natural product derived from the Japanese marine sponge Halichondria okadai 4, 3
• This synthetic derivation allows for practical pharmaceutical production while maintaining the unique mechanism of action 2