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Endocrine Abstracts (2025) 110 P70 | DOI: 10.1530/endoabs.110.P70

1University of Milan, Department of Clinical Sciences and Community Health, Milan, Italy; 2University of Milan, PhD Programme in Experimental Medicine, Milan, Italy; 3University of Birmingham, College of Medicine and Health, Birmingham, UK; 4University Hospital Würzburg, University of Würzburg, Department of Internal Medicine I, Division of Endocrinology and Diabetes, Würzburg, Germany; 5University Hospital Zurich (USZ), University of Zurich (UZH), Department of Endocrinology, Diabetology and Clinical Nutrition, Zurich, Switzerland; 6University Hospital Carl Gustav Carus Dresden, Medizinische Klinik und Poliklinik III, Dresden, Germany; 7University of Brescia, Section of Pharmacology, Department of Molecular and Translational Medicine,, Brescia, Italy; 8ASST Spedali Civili di Brescia, Medical Oncology Unit, Brescia, Italy; 9University of Brescia, Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, Brescia, Italy; 10Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan, Endocrinology Unit, Milan, Italy; 11Birmingham Health Partners, Centre for Endocrinology, Diabetes and Metabolism, Birmingham, UK


JOINT1256

Background: Adrenocortical carcinomas (ACC) are highly aggressive malignancies with limited treatment options. Polo-like kinase 1 (PLK1) and cyclin-dependent kinases (CDKs) 1/2/4 are among the most overexpressed genes in ACC human samples. We have previously demonstrated the efficacy of PBD-targeting PLK1 inhibitor (PLK1i) poloxin in ACC cell lines (H295R, MUC-1, CU-ACC2).

Aims and methods: We tested the efficacy of 1) two PLK1i, i.e. the polo-box domain (PBD)-targeting poloxin and the kinase domain (KD)-targeting plogosertib; 2) two CDK inhibitors (CDKi), i.e. dinaciclib (targeting preferentially CDK1/2) and the CDK1-cyclin B1 inhibitor cucurbitacin E (CurE); 3) the combination of plogosertib and dinaciclib. Their efficacy was evaluated in four ACC cell lines, including H295R, MUC-1, and the newly generated TVBF-7 and JIL-2266. Increasing drug concentrations for 72 h. Cell proliferation and apoptosis were assessed by BrdU incorporation and caspase 3/7 activity, respectively, compared to basal condition. The “SynergyFinder” tool was used to analyse two-drugs combinations.

Results: PLK1i poloxin reduced proliferation at very high doses, achieving a maximum effect at 100μM (P<0.01 in MUC-1 and TVBF-7; P<0.001 in H295R and JIL-2266), and increased apoptosis at 10μM (P<0.05 for all). At considerably lower concentrations, plogosertib dose-dependently reduced cell proliferation (P<0.05 at 100 nM in MUC-1 and JIL-2266; P<0.01 at 750 nM in H295R and TVBF-7) and increased apoptosis (P<0.05 for H295R, TVBF-7, and JIL-2266 at 1μM). CDKi dinaciclib markedly reduced cell proliferation at low nanomolar doses (P<0.05 at 20 nM in MUC-1 and JIL-2266, and at 100 nM in TVBF-7; P<0.01 at 100 nM in H295R), and increased apoptosis (P<0.05 in MUC-1, TVBF-7, and JIL-2266 at 200 nM). CurE dose-dependently reduced proliferation in all ACC cells, but its effects were less pronounced than dinaciclib (P<0.05 at 100 nM in MUC-1 and TVBF-7; P<0.01 at 100 nM in H295R and JIL-2266). In line with the observed differences in treatment sensitivity among cell lines, qRT-PCR analysis showed that CDK1/2 and PLK1 mRNA expression was particularly high in MUC-1 and JIL-2266. Synergistic suppression of cell proliferation by combined treatment with PLK1i plogosertib and CDKi dinaciclib was observed in H295R (P<0.05) and TVBF-7 (P<0.01) cell lines.

Conclusion: Plogosertib and dinaciclib were the most effective inhibitors in all cell lines, representing interesting novel targeted treatment options for ACC. Moreover, the combination of these drugs showed a synergistic effect, suggesting a potential benefit of using both PLK1i and multi CDKi that need to be further investigated in vivo.

Volume 110

Joint Congress of the European Society for Paediatric Endocrinology (ESPE) and the European Society of Endocrinology (ESE) 2025: Connecting Endocrinology Across the Life Course

European Society of Endocrinology 
European Society for Paediatric Endocrinology 

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