Pan-CDK and PLK1 inhibitors as a novel approach for targeted treatment of adrenocortical carcinomas
Emanuela Esposito1, Emma Nozza1, Anna Maria Barbieri1
1Department of Clinical Sciences and Community Health, University of Milan, Milan, 20122, Italy.
Abstract:
Background Adrenocortical carcinomas (ACC) are aggressive cancers with limited therapeutic options. Cyclin-dependent kinases (CDKs) 1/2/4 and polo-like kinase 1 (PLK1) are upregulated in ACC, suggesting their role as potential targets. Objective This study investigated the anti-tumour efficacy of the pan-CDK inhibitors (CDKi) dinaciclib, AT7519, and SNS-032; the CDK1-cyclin B1 inhibitor cucurbitacin E (curE); the PLK1 inhibitors (PLK1i) poloxin and plogosertib; and selected combination strategies in four genetically heterogeneous ACC cell lines (NCI-H295R, JIL-2266, MUC-1, and TVBF-7) and primary cultures. Results ACC cells showed marked CDK1/2/4 and PLK1 transcript and protein upregulation compared to normal adrenal gland. Dinaciclib reduced cell growth and induced apoptosis at low nanomolar doses. CurE induced weaker pro-apoptotic effects, whereas AT7519 and SNS-032 displayed activity only in JIL-2266 and MUC-1. Among PLK1i, plogosertib impaired proliferation and increased apoptosis in a nanomolar range. Dinaciclib-plogosertib combination produced the highest synergistic anti-proliferative effects in NCI-H295R and TVBF-7. In steroidogenic NCI-H295R cells, dinaciclib lowered cortisol secretion and downregulated CYP11A1, CYP17A1, CYP21A2, SF-1, and GR transcripts, as well as GR protein expression. In parallel, dinaciclib broadly suppressed CDK1/2 axis and their downstream signalling proteins, including cyclin E1 and p21Waf1/Cip1, consistent with G1/S blockade. Plogosertib increased p-CDK1(Tyr15), cyclin B1, and γ-H2AX levels, indicative of DNA damage and mitotic stress. Conclusions These results identify dinaciclib and plogosertib as the most effective inhibitors across all ACC models tested. Their simultaneous action on multiple checkpoints, alongside with their synergistic effect in selected cell lines, suggest a potential benefit of their use in ACC that needs to be further investigated in vivo.
Insights
Dinaciclib and plogosertib show significant anti-tumour effects against adrenocortical carcinoma (ACC) by targeting cell cycle kinases. Combination therapy demonstrates synergistic potential for treating this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited treatment options.
- Key cell cycle regulators, including cyclin-dependent kinases (CDKs) and polo-like kinase 1 (PLK1), are frequently upregulated in ACC, presenting potential therapeutic targets.
Purpose of the Study:
- To investigate the anti-tumour efficacy of various CDK inhibitors (dinaciclib, AT7519, SNS-032, cucurbitacin E) and PLK1 inhibitors (poloxin, plogosertib) in ACC.
- To evaluate the synergistic effects of combined inhibition strategies in ACC cell lines and primary cultures.
Main Methods:
- Treatment of genetically diverse ACC cell lines (NCI-H295R, JIL-2266, MUC-1, TVBF-7) and primary cultures with selected inhibitors.
- Assessment of cell growth, apoptosis, and specific molecular targets (e.g., cortisol secretion, gene/protein expression of cell cycle regulators and DNA damage markers).
- Evaluation of synergistic anti-proliferative effects of combination therapies, particularly dinaciclib and plogosertib.
Main Results:
- ACC cells exhibited significant upregulation of CDK1/2/4 and PLK1 compared to normal adrenal tissue.
- Dinaciclib demonstrated potent anti-proliferative and pro-apoptotic effects at nanomolar concentrations, while plogosertib impaired proliferation and induced apoptosis.
- The combination of dinaciclib and plogosertib exhibited the highest synergistic anti-proliferative activity in specific ACC models, with dinaciclib also reducing cortisol secretion and downregulating key steroidogenic genes.
Conclusions:
- Dinaciclib and plogosertib are identified as the most effective single agents against ACC models tested.
- The combination of dinaciclib and plogosertib shows significant synergistic anti-tumour effects, targeting multiple cell cycle checkpoints and inducing DNA damage.
- These findings suggest a promising therapeutic potential for dinaciclib and plogosertib, alone or in combination, in adrenocortical carcinoma treatment, warranting further in vivo investigation.
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