Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited treatment options. Polo-like kinase 1 (PLK1) is a promising drug target; PLK1 inhibitors (PLK1i) have been investigated in solid cancers and are more effective in TP53-mutated cases. We evaluated PLK1 expression in ACC samples and the efficacy of two PLK1i in ACC cell lines with different genetic backgrounds. PLK1 protein expression was investigated by immunohistochemistry in tissue samples and correlated with clinical data. The efficacy of rigosertib (RGS), targeting RAS/PI3K, CDKs and PLKs, and poloxin (Pol), specifically targeting the PLK1 polo-box domain, was tested in TP53-mutated NCI-H295R, MUC-1, and CU-ACC2 cells and in TP53 wild-type CU-ACC1. Effects on proliferation, apoptosis, and viability were determined. PLK1 immunostaining was stronger in TP53-mutated ACC samples vs wild-type (P = 0.0017). High PLK1 expression together with TP53 mutations correlated with shorter progression-free survival (P= 0.041). NCI-H295R showed a time- and dose-dependent reduction in proliferation with both PLK1i (P< 0.05at 100 nM RGS and 30 µM Pol). In MUC-1, a less pronounced decrease was observed (P< 0.05at 1000 nM RGS and 100 µM Pol). 100 nM RGS increased apoptosis in NCI-H295R (P< 0.001), with no effect on MUC-1. CU-ACC2 apoptosis was induced only at high concentrations (P < 0.05 at 3000 nM RGS and 100 µM Pol), while proliferation decreased at 1000 nM RGS and 30 µM Pol. CU-ACC1 proliferation reduced, and apoptosis increased, only at 100 µM Pol. TP53-mutated ACC cell lines demonstrated better response to PLK1i than wild-type CU-ACC1. These data suggest PLK1i may be a promising targeted treatment of a subset of ACC patients, pre-selected according to tumour genetic signature.

肾上腺皮质癌（ACC）是一种侵袭性恶性肿瘤，治疗选择有限。Polo 样激酶 1 (PLK1) 是一个有前途的药物靶点；PLK1 抑制剂 (PLK1i) 已在实体癌中进行了研究，并且对TP53突变病例更有效。我们评估了 ACC 样本中的 PLK1 表达以及两种 PLK1i 在不同遗传背景的 ACC 细胞系中的功效。通过免疫组织化学研究组织样本中的 PLK1 蛋白表达并与临床数据相关。在TP53突变的 NCI-H295R、MUC-1 和 CU-ACC2中测试了针对 RAS/PI3K、CDK 和 PLK 的 rigosertib (RGS) 以及专门针对 PLK1 polo-box 结构域的 poloxin (Pol) 的功效细胞和TP53野生型 CU-ACC1 中。确定了对增殖、凋亡和活力的影响。与野生型相比，TP53突变 ACC 样本中的 PLK1 免疫染色更强（ P = 0.0017）。高 PLK1 表达和TP53突变与较短的无进展生存期相关 ( P = 0.041)。NCI-H295R 在 PLK1i 的作用下表现出时间和剂量依赖性的增殖减少（100 nM RGS 和 30 µM Pol 时P < 0.05）。在 MUC-1 中，观察到不太明显的降低（1000 nM RGS 和 100 µM Pol 时P < 0.05）。100 nM RGS 增加 NCI-H295R 中的细胞凋亡（P < 0.001），但对 MUC-1 没有影响。CU-ACC2 细胞凋亡仅在高浓度下诱导（3000 nM RGS 和 100 µM Pol 时P < 0.05），而增殖在 1000 nM RGS 和 30 µM Pol 时下降。仅在 100 µM Pol 时，CU-ACC1 增殖减少，细胞凋亡增加。TP53突变的 ACC 细胞系表现出比野生型 CU-ACC1 更好的对 PLK1i 的反应。这些数据表明 PLK1i 可能是针对 ACC 患者子集的一种有前途的靶向治疗方法，根据肿瘤遗传特征进行预先选择。