Pan-CDK and PLK1 inhibitors as a novel approach for targeted treatment of adrenocortical carcinomas

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. 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, TVBF-7) and primary cultures. 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. 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.