Abstract 901: Mitotic kinase inhibitors synergize with PI3K and Akt inhibitors in a novel model of anaplastic thyroid carcinomas

Abstract

Abstract Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to any therapeutic approach. We have generated a mouse model in which the simultaneous selective activation of the PI3K pathway and inactivation of p53 in the thyroid epithelial cells leads to the development of ATCs. These tumors display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion and distant metastases. Expression profiling of the murine ATCs reveals a significant overlap with genes found deregulated in human ATC, including genes involved in mitosis control, such as Aurora kinase A (AURKA), its co-activator TPX2, and Polo like kinase-1 (PLK1). These proteins are crucial driving forces for normal mitotic spindle formation, centrosome maturation and separation, and their overexpression has been demonstrated in a wide range of tumors. MLN8237 (AURKA inhibitor), TAK960 and GSK461364 (PLK1 inhibitors) are a promising new generation of anti-mitotic agents. We show that these molecules inhibit cell proliferation and induce cell death in mouse ATC-derived cell lines and in the human ATC cell lines CAL62 and C643. A dose-dependent decrease in the degree of chromosome alignment and spindle bipolarity during mitosis is observed after the treatments, together with a change in mitotic index indicated by the decrease of the mitotic marker pHisH3. FACS analysis reveals a G2/M phase arrest followed by apoptosis. Furthermore, small molecule inhibitors of PI3K or AKT potently synergize with these anti-mitotic compounds. Taken together these data suggest that AURKA and PLK1 inhibitors are promising therapeutic agents against undifferentiated thyroid carcinoma cells, and that concurrent inhibition of key driver pathways is a viable option to increase efficacy in this otherwise invariably lethal cancer. 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 901. doi:1538-7445.AM2012-901