Targeting the centrosome and polo-like kinase 4 in osteosarcoma.

ABSTRACT

It has been historically uncertain if extra centrosomes are a cause or consequence of tumorigenesis. Experiments have recently established that overexpression of polo-like kinase 4 (PLK4) promotes centrosome amplification with consequential promotion of cellular aneuploidy. Furthermore, centrosome amplification drives spontaneous tumorigenesis in mice. Tissues lacking normal functional p53 tolerate extra centrosomes, whereas p53 proficient tissues initiate proliferative arrest in this circumstance. Extra centrosomes trigger activation of the multi-protein PIDDosome complex, with Caspase-2 effecting cleavage of the p53-negative regulator mouse double minute 2, consequent stabilization of p53 and p21-dependent arrest of the cell cycle. The co-occurrence of cellular aneuploidy, complex chromosomal rearrangements and p53 dysfunction is a striking feature of some osteosarcomas. It is postulated that small-molecule PLK4 inhibitors such as CFI-400945, which are in development, may have utility in osteosarcoma given these findings.