SFEBES2021 Oral Poster Presentations Adrenal and Cardiovascular (4 abstracts)
PLK1 inhibitors as a new targeted treatment for adrenocortical carcinoma
Emily Warmington 1 , Gabrielle Smith 1 , Vasileios Chortis 1 , Sana Khan 1 , Juliane Lippert 2 , Constanze Hantel 3,4 , Raimunde Liang 2 , Katja Kiseljak-Vassiliades 5 , Margaret Wierman 5 , Barbara Altieri 2 , Martin Fassnacht 2 , Paul Foster 1 & Cristina Ronchi 1,2
1Institute of Metabolism and System Research, Birmingham, United Kingdom; 2University Hospital of Wuerzburg, Wuerzburg, Germany; 3University Hospital Zurich, Zurich, Switzerland; 4University Hospital Carl Gustav Carus, Dresden, Germany; 5University of Colorado, Denver, USA
Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited treatment options. We identified polo-like kinase 1 (PLK1) as one of the most overexpressed genes and potential drug target in ACC. PLK1 inhibitors (PLK1i) are under evaluation in clinical trials for other malignancies, being more effective in TP53-mutated tumours. Here we test PLK1i efficacy in four ACC cell lines with different genetic background. Efficacy of three PLK1i (i.e. Volasertib, Vol, multi-targeting Rigosertib, RGS, and PBD-PLK1-specific Poloxin) was evaluated in NCI-H295R (TP53 deletion) and MUC1 (frameshift TP53 mutation) cell lines. RGS and Poloxin were also tested in CU-ACC1 (TP53 wild-type) and CU-ACC2 (missense TP53 mutation) cells. Increasing concentrations were used at different time-points (24h-48h-72h) and compared with vehicle control. Cell proliferation was analysed using DNA fluorescence and cell apoptosis by Caspase Glo 3/7 assay. NCI-H295R cells showed a significant time- and dose-dependent reduction of cell proliferation after 72h with all PLK1i with maximum effect at 100nM Vol and RGS and 10µM Poloxin (P < 0.05). In MUC1 cells a less pronounced effect on proliferation was observed with best effect at 72h 1000 nM RGS and 48h/72h 30uM Poloxin (P < 0.001). Regarding cell apoptosis, NCI-H295R cells showed significant increase at 100nM of both Vol and RGS (P < 0.01), but not with Poloxin. No effect was observed in MUC1 cells. In CU-ACC2 cells, both RGS and Poloxin had limited effect on cell proliferation (P < 0.05 at 1000nM and P < 0.0001 30µM, respectively) and apoptosis (P < 0.05 only at 3000nM RGS). Finally, in TP53 WT CU-ACC1 cells, a reduced proliferation was observed only with 100 µM Poloxin (P < 0.001). In conclusion, ACC cells with TP53 variants demonstrated greater response to PLK1i than TP53 WT CU-ACC1, with the most impressive efficacy seen in NCI-H295R. Thus, PLK1i might represent a promising targeted treatment of a subset of ACC patients with a specific tumour molecular pattern.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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