Inhibition of Polo-like Kinase 1 by HMN-214 Blocks Cell Cycle Progression and Inhibits Neuroblastoma Growth.

Abstract

Polo-like kinase 1 (PLK1) is an essential cell cycle mitotic kinase component that plays an important role in cell cycle progression and has been reported to be involved in various cancers, including neuroblastoma (NB). PLK1 also regulates G2/M transition, chromosomal segregation, spindle assembly maturation, and mitotic exit. NB is an early embryonic-stage heterogeneous solid tumor and accounts for 15% of all pediatric cancer-related deaths. Therefore, we aimed to develop a targeting strategy for PLK1 by repurposing HMN-214 in NB. HMN-214 is a prodrug of HMN-176 and is known to selectively interfere with PLK1 function. In the present study, we performed the transcriptomic analysis of a large cohort of primary NB patient samples and revealed that PLK1 expression is inversely correlated with the overall survival of NB patients. Additionally, we found that PLK1 strongly correlates with NB disease and stage progression. HMN-214 significantly inhibited NB proliferation and colony formation in both MYCN-amplified and -nonamplified cell lines in a dose-dependent manner. Furthermore, HMN-214 induces apoptosis and significantly obstructs the cell cycle at the G2/M phase in NB cells by inhibiting multiple cell-cycle-related genes, such as PLK1, WEE1, CDK1, CDK2, Cyclin B1, CHK1, and CHK2. HMN-214 significantly inhibits cell cycle regulator CDK1 and the phosphorylation and activation of PLK1 in NB. In the NB 3D spheroid tumor model, HMN-214 significantly and in a dose-dependent manner inhibits spheroid tumor mass and growth. Overall, our study highlights that targeting PLK1 using HMN-214 is a novel therapeutic approach for NB.