Chromosomal instability (CIN) and
aneuploidy are commonly observed in the vast majority of human solid
tumors and in many
hematological malignancies. These features are considered defining characteristics of human breast, bladder and
kidney cancers since they markedly exceed a 50%
aneuploidy frequency. The detection of persistent mitotic
kinase over-expression, particularly the Aurora family, and centrosome amplification in precursor/pre-malignant stages, strongly implicate these molecular changes in precipitating the
aneuploidy seen in many human
neoplasms. Mitotic spindle checkpoint defects may also lead to
aneuploid tumors. However, the sustained over-expression and activity of various members of the mitotic
kinase families, including Aurora (Aur) (A, B, C), Polo-like (Plk1-4), and Nek (NIMA1-11) in diverse human
tumors strongly indicate that these entities are intimately involved in the development of errors in centrosome
duplication, chromosome segregation, and cytokinesis. Mitotic
kinases have also been implicated in regulating the centrosome cycle, spindle checkpoint and microtubule-kinetochore attachment, spindle assembly, and chromosome condensation. These mitotic
kinases are modulated by de-novo synthesis, stability factors, phosphorylation, and
ubiquitin-dependent proteolysis. They, in turn, phosphorylate a myriad of centrosomal/mitotic
protein substrates, and have the ability to behave as oncogenes (i.e. Aur-A, Plk-1), providing a compelling link between errors in mitosis and oncogenic processes. The recent development of selective small molecule inhibitors of
Aurora kinases, in particular, will provide useful tools to ascertain more precisely their role in
cancer development. Potent inhibitors of mitotic
kinases, when fully developed, have the promise to be effective agents against
tumor growth, and possibly,
tumor prevention as well.