Dual inhibition of PLK1 and multiple CDKs: a novel approach for the treatment of adrenocortical carcinomas

Emanuela Esposito; Lucy Beevors; Vasileios Chortis; Laura-Sophie Landwehr; Constanze Hantel; Sandra Sigala; Erika Peverelli; Giovanna Mantovani; Paul A. Foster; Ronchi Cristina L

doi:10.1530/endoabs.107.010

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Endocrine Abstracts (2024) 107 010 | DOI: 10.1530/endoabs.107.010

IACS9 9th International Adrenal Cancer Symposium 2024 Abstracts (18 abstracts)

Dual inhibition of PLK1 and multiple CDKs: a novel approach for the treatment of adrenocortical carcinomas

Emanuela Esposito ^1,2 , Lucy Beevors ³ , Vasileios Chortis ³ , Laura-Sophie Landwehr ⁴ , Constanze Hantel ^5,6 , Sandra Sigala ⁷ , Erika Peverelli ^1,8 , Giovanna Mantovani ^1,8 , Paul A. Foster ^3,9 & Cristina L Ronchi ^3,9

Author affiliations

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

Adrenocortical carcinomas (ACC) are highly aggressive tumors 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 the polo-box domain (PBD)-targeting PLK1 inhibitor (PLK1i) Poloxin in ACC cell lines (H295R, MUC-1, CU-ACC2). Here, we tested 1) the efficacy of Poloxin and the kinase domain (KD)-targeting PLK1i Plogosertib; 2) the efficacy of CDK1/2 inhibitor (CDKi) Dinaciclib, and CDK1-cyclin B1 inhibitor Cucurbitacin E; 3) the combinatorial effect of Plogosertib and Dinaciclib on cell proliferation. Experiments were carried out in four cell lines including H295R, MUC-1, and recently generated TVBF-7 and JIL-2266. Increasing drugs concentrations were used for 72h. Cell proliferation and apoptosis were assessed by BrdU incorporation and caspase 3/7 activity, respectively. Two-drugs combination data were analysed by the “SynergyFinder” tool. PLK1i Poloxin reduced cell proliferation at very high doses, reaching 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 cell lines). At much lower doses, Plogosertib induced a dose-dependent reduction of cell proliferation (P < 0.05 at 100nM in MUC-1 and JIL-2266; P < 0.01 at 750nM in H295R and TVBF-7) and an increase of apoptosis (P < 0.05 for H295R, TVBF-7, and JIL-2266 at 1μM). CDKi Dinaciclib drastically reduced cell proliferation at low nanomolar concentrations (P < 0.05 at 20nM in MUC-1 and JIL-2266, and at 100nM 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 200nM). Cucurbitacin E reduced proliferation in all ACC cells, but its effects were less pronounced than Dinaciclib. Synergistic inhibition 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) cells. In conclusion, we identified Plogosertib and Dinaciclib as the most effective inhibitors on all cell lines, among those selected, therefore representing interesting novel 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 to increase therapeutic efficacy and to reduce potential side effects.