PLK1 inhibitors as a new targeted treatment for adrenocortical carcinoma

Abstract

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 < 0.05 at 100 nM RGS and 30 μM Pol). In MUC-1, a less pronounced decrease was observed (P < 0.05 at 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.

Keywords

• adrenocortical carcinoma
• polo-like kinase 1
• molecular-targeted therapy