Abstract 3757: CR8, a novel CDK inhibitor, enhances vandetanib activity in a human medullary thyroid carcinoma model

Abstract

Abstract Introduction: CR8 (ManRos Therapeutics) is a novel inhibitor of cyclin-dependent kinases (CDKs) that selectively targets CDK1/2/3/5/7/9. CDK inhibitors have already shown potent antitumoral activity. Recently, vandetanib (Astra Zeneca), a tyrosine-kinase inhibitor, was approved in the U.S. for the treatment of adult patients with metastatic Medullary Thyroid Carcinoma (MTC). The absence of complete tumor responses justifies the development of new therapeutic options. The aim of this study was to investigate the preclinical activity of CR8 alone and in combination with vandetanib in a MTC model. Materials and Methods: The human MTC TT cell line, bearing a RETC634W activating mutation, was cultured in the absence or the presence of CR8 (10-10 000 nM) and/or vandetanib over 6 days. Cell proliferation was assessed by WST-1 assay. Activation of RET, PP1α and oncogenic pathways (PI3K/AKT, MEK/p44-42) was analyzed by western-immunoblotting. Calcitonin secretion in cell culture media was measured by ELISA. Results: Both CR8 and vandetanib when used alone strongly inhibit TT cell proliferation at day 3 of treatment. Addition of CR8 (10 nM) enhances the antiproliferative activity of low vandetanib concentrations. As expected, vandetanib alone inhibits RET, MAPK and AKT phosphorylation and CR8 inhibits PP1α. Interestingly, CR8 alone induces activation of RET, MAPK and AKT phosphorylation, and the addition of vandetanib (>100 nM) inhibits RET signalling pathways. At day 3 of treatment, vandetanib (>100 nM) and CR8 (100 nM) reduced and induced calcitonin secretion, respectively. Conclusion: CR8 displays an antiproliferative effect on TT cells and enhances the antiproliferative activity of vandetanib. CR8 acts by inhibiting PP1α and, surprisingly, induces an activation of RET and stimulates calcitonin production. These results suggest that the combination of vandetanib with CDKs inhibitors such as CR8 may be of value to improve therapeutic response. 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 3757. doi:1538-7445.AM2012-3757