Identifying Anti-cancer Effects and Exploring the Mechanism of an MPS1/TTK Inhibitor in Gastric Cancer.

[PURPOSE] This study aimed to identify the anti-cancer effect and investigate the underlying mechanism of MPS1/TTK (monopolar spindle 1; also known as threonine tyrosine kinase) inhibitor in gastric cancer (GC) cell lines.

[MATERIALS AND METHODS] This study used compound-9, a highly selective MPS1/TTK inhibitor, to evaluate its anti-cancer effects on GC cell lines. Cell viability assay was performed to determine sensitivity to the inhibitor. Cell cycle analysis and apoptosis assays were performed using Flow cytometry to evaluate the effects of the inhibitor. Protein-expression levels were analyzed through western blotting after the inhibitor treatment.

[RESULTS] The Epstein-Barr virus and microsatellite-instable-high groups tended to be sensitive to the inhibitor, while the genomically stable (GS)-likely group tended to be moderate-to-resistant. In contrast, the chromosomal instability (CIN)-likely group was extremely sensitive or resistant. Within the CIN group, TP53WT cell lines were sensitive, whereas TP53MUT cell lines were sensitive or resistant. Upon treatment of the inhibitor, the TP53WT-sensitive cell line underwent cell death more rapidly compared to the TP53MUT-sensitive cell line. In contrast, the TP53MUT-sensitive cell experienced higher levels of aneuploidy or polyploidy and underwent cell death at later time point than the TP53WT-sensitive cell line. The TP53MUT-resistant line can tolerate aneuploidy or polyploidy and exhibits drug resistance.

[CONCLUSION] Our study explores the potential of an MPS1/TTK inhibitor, compound-9, as a targeted therapy in GC cells and investigates its mechanism of action.