SUN-LB22 PLK1 as a New Treatment Target for Adrenocortical Carcinoma

Abstract

Background: Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited medical treatment options. We previously identified polo-like kinase 1 (PLK1) as one of most overexpressed genes in ACC; thus PLK1 represents a potential treatment target for this cancer type. Some PLK1 inhibitors are under evaluation in clinical trials for other solid organ malignancies, and seem to be more effective in TP53 mutated tumours. The aim of this study was to evaluate PLK1 protein levels in a large series of ACC and assess the in vitroefficacy of PLK1 inhibitors in two different ACC cell lines. Methods: 104 formalin-fixed paraffin-embedded ACC tissue samples with available genetic data were investigated. Nuclear PLK1 protein expression was evaluated by immunohistochemistry and a semi-quantitative H-score was calculated. PLK1 expression levels were correlated to clinical and histological parameters. Efficacy of PLK1-specific inhibitor Volasertib (0-200 nM) was tested in the standard NCI-H295R ACCcell line, which presents PLK-1 overexpression and a large TP53 deletion, and in the newly established MUC1 cell line, which bears a frameshift mutation in TP53. Cell proliferation was analysed using DNA fluorescence and cell apoptosis by Caspase Glo 3/7 assay. Results: Nuclear PLK1 expression was classified as high in 59% of ACC samples, with a significant difference noted between TP53-mutated (n=24) and wild-type (n=80) cases (87.5 vs 51%, p<0.01). PLK1 levels did not correlate with either progression-free or overall survival. H295R cells showed a significant time- and dose-dependent reduction of cell proliferation compared to vehicle control after 72h of Volasertib treatment (p<0.005 per trend, p=0.01 by 200nM by non-parametric two-way ANOVA). A less pronounced and non-significant trend towards inhibited proliferation was observed in MUC1 cells. Cell apoptosis was significantly higher in the H295R cells treated with 175nM and 200nM Volasertib when compared to control (p<0.05), while there was no significant difference in MUC1 cells. Conclusion:In this pilot study, we propose PLK1 inhibitors as promising candidates for treatment of a subset of ACC patients that may be pre-selected according to the tumour molecular pattern. We plan to extend functional experiments to further PLK1 inhibitors, including additional ACC cell lines with a different molecular profile.