In this study, we observed an association between high tumor expression of Eg5 and poor HCC prognosis. The 24-month OS rate of patients with low and high Eg5 expression of 75% and 41.7% differed substantially. Even after adjustment for other clinicopathological variables, Eg5 expression remained an independent predictor of OS and DFS. The preclinical HCC models demonstrated the therapeutic potential of Eg5 inhibition, through a novel Eg5 inhibitor LGI-147. Eg5 inhibition by LGI-147 interfered with mitosis, halted the cell cycle, and induced apoptosis in the HCC cells. The HCC xenograft model also demonstrated the in vivo antitumor efficacy of LGI-147.
Inhibition of cell proliferation through mitosis is a clinically effective anticancer intervention . As our previous studies have demonstrated, the overexpression of Aurora kinases A and B, essential mitotic kinases, in HCC cells is associated with poor HCC prognosis [7, 9]. Furthermore, Aurora kinase inhibitors have potent anticancer effects in human HCC [7, 9]. Elucidation of the prognostic significance of Eg5 expression and the antitumor efficacy of specific Eg5 inhibitors is essential to establish Eg5 as a therapeutic target for HCC. Therefore, the findings of the present study provide a rationale for the clinical development of specific Eg5 inhibitors for HCC treatment. Our findings regarding the prognostic value of Eg5 expression are generally consistent with those of a previous study , although that study did not analyze DFS and used immunohistochemical staining, rather than quantified RNA expression, to evaluate tumor Eg5 expression levels.
The past decade has seen the identification of multiple anticancer small-molecule inhibitors targeting mitotic machinery, including Aurora kinases, Polo-like kinase 1, Eg5, and CENP-E. Their cellular consequences are typically disturbance of the cell cycle, suppression of cell proliferation, and induction of apoptosis at mitotic phase or following mitotic slippage . Eg5 is a promising anticancer therapeutic target because, as with other kinesins such as CENP-E, it is critically involved in centrosome maturation, spindle assembly, chromosome segregation, and cytokinesis . In the current study, we used LGI-147, a specific Eg5 inhibitor that did not inhibit the activity of other kinesins such as CENP-E, MKLP-1, and BimC. The IC50 of LGI-147 on cell viability at the pM level was extremely low. The therapeutic potential of other Eg5 inhibitors such as AZD4877 [26, 27] and filanesib [28–30] has been demonstrated in several phase I or II clinical trials for cancers other than HCC. Our findings may provide a basis for the development of LGI-147 or other Eg5 inhibitors as HCC therapeutics.
Our study had some limitations. First, we only used one method of Eg5 inhibition because we did not have access to Eg5 inhibitors other than LGI-147. However, as mentioned, LGI-147 had high specificity; therefore, the possibility of an off-target effect of LGI-147 as the primary mechanism is low. Second, we did not examine the peripheral blood cell counts of mice under LGI-147 treatment. Because mitosis inhibitors may affect all dividing cells, bone marrow suppression can be primary toxicity. However, such problems can be addressed in phase 1 clinical trials or resolved through scheduling.