Abstract 2823: PHA-739358, a pan-Aurora kinase inhibitor, induces apoptosis and inhibits invasion in melanoma cell lines

Abstract

Abstract Cutaneous melanoma (CM) is the most lethal form of skin cancer and is highly invasive and markedly resistant to conventional therapy. The incidence of malignant melanoma has been increasing worldwide for the past three decades, however, the standard care for patients with metastatic melanoma has not changed significantly, therefore, new strategies for treatment of metastatic melanoma are urgently needed. Significant insights have recently been gained into the molecular events underpinning the development of melanoma. Aurora kinases play an essential role as key mitotic regulators, controlling chromosome alignment, segregation, centrosomal maturation, mitotic spindle formation, and cytokinesis during mitosis, and are frequently overexpressed in various human cancers including that of CM making them ideal targets for anti-cancer therapy. Several small molecule inhibitors of the aurora kinases have been developed and tested in vivo and in vitro, and some of them have shown promising clinical efficacy in a number of early phaseI/II clinical trials. Among those, one of the most advanced clinical compounds currently is PHA-739358 (PHA). The goal of this study is to investigate the anti-proliferative and anti-invasive features of PHA in three melanoma cell lines including WM3211, Lu1205, and SK-Mel28. The results showed a time- and dose- dependent growth inhibition in all the cell lines tested with low μM IC50s upon PHA treatment, and significant induction of caspase activity was observed as well. FACScan cell cycle analysis showed significant induction of G2/M population of cells in all three cell lines and increased polyploidy proportion of cells in WM3211 cell line. For the first time, we showed that PHA inhibits melanoma cell invasion in a dose- and time- dependent manor using a Matrigel Invasion Assay. More interestingly, addition of PHA enhanced Temozolomide (TMZ)-induced caspase activation in melanoma cell lines indicating a potential combination therapeutic strategy for the treatment of melanoma. Thus, targeting aurora kianses with PHA is a promising therapeutic strategy administered alone or in combination with TMZ for patients with advanced stages of CM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2823. doi:1538-7445.AM2012-2823