Ability of selective small molecule inhibitors of Aurora-A and Aurora-B in inhibiting tumorigenicity of anaplastic thyroid carcinoma-derived cell lines.

Abstract

Aurora kinases are a family of serine/threonine kinases which play an essential role in cell division. Their aberrant expression and/or function bring about severe mitotic abnormalities resulting in either cell death or aneuploidy. Aurora kinases are often found overexpressed in a variety of malignancies among which thyroid cancers, and particularly in the most aggressive form, the anaplastic thyroid carcinoma (ATC). In previous studies we demonstrated the in vitro efficacy of small molecule inhibitors of Aurora kinases in restraining cell growth and survival of different ATC derived cell lines. In the present preclinical study we sought to establish which of the Auroras is the best drug target for ATC therapy. To this end, the effects of two selective inhibitors of Aurora-A (MLN8237/Alisertib) and Aurora-B (AZD1152/Barasertib) have been analyzed on a panel of human ATC derived cell lines (CAL-62, BHT-101, 8305C, 8505C). Both inhibitors reduced proliferation of the different cancer cells in a time- and dose-dependent manner, with IC50 ranges of 17.5-86 nM for MLN8237 and of 59-380 nM for AZD1152. Western blot experiments demonstrated that concentrations of inhibitors exerting maximal anti-proliferative effects were still selective for Aurora-A or -B. Moreover, as evidenced by immunofluorescence and time-lapse experiments, each inhibitor induced a distinct cellular phenotype depending on the kinase targeted. Polyploidy increased significantly in all the cell lines treated with AZD1152 and in 2 out of 4 lines treated with MLN8237, while apoptosis was induced by both treatments in all cells. Both drugs were also capable to block anchorage-independent ATC cell growth. In conclusion, our results indicate that selective inhibitors of Aurora-A or Aurora-B display similar efficacy in inhibiting tumorigenicity of ATC-derived cell lines and they might represent new therapeutic options for ATC treatment