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Targeted Gene Expression Profile Reveals CDK4 as Therapeutic Target for Selected Patients With Adrenocortical
Raimunde Liang1, Isabel Weigand1, Juliane Lippert1,2
1Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital of Wuerzburg, Würzburg, Germany.
Abstract:
Adrenocortical carcinomas (ACC) are aggressive tumors with a heterogeneous prognosis and limited therapeutic options for advanced stages. This study aims to identify novel drug targets for a personalized treatment in ACC. RNA was isolated from 40 formalin-fixed paraffin-embedded ACC samples. We evaluated gene expression of 84 known cancer drug targets by reverse transcriptase quantitative real time-PCR and calculated fold change using 5 normal adrenal glands as reference (overexpression by fold change >2.0). The most promising candidate cyclin-dependent kinase 4 (CDK4) was investigated at protein level in 104 ACC samples and tested by in vitro experiments in two ACC cell lines (NCI-H295R and MUC1). The most frequently overexpressed genes were TOP2A (100% of cases, median fold change = 16.5), IGF2 (95%, fold change = 52.9), CDK1 (80%, fold change = 6.7), CDK4 (62%, fold change = 2.6), PLK4 (60%, fold change = 2.8), and PLK1 (52%, fold change = 2.3). CDK4 was chosen for functional validation, as it is actionable by approved CDK4/6-inhibitors (e.g., palbociclib). Nuclear immunostaining of CDK4 significantly correlated with mRNA expression (R = 0.52, P < 0.005). We exposed both NCI-H295R and MUC1 cell lines to palbociclib and found a concentration- and time-dependent reduction of cell viability, which was more pronounced in the NCI-H295R cells in line with higher CDK4 expression. Furthermore, we tested palbociclib in combination with insulin-like growth factor 1/insulin receptor inhibitor linsitinib showing an additive effect. In conclusion, we demonstrate that RNA profiling is useful to discover potential drug targets and that CDK4/6 inhibitors are promising candidates for treatment of selected patients with ACC.
Insights
This study identifies cyclin-dependent kinase 4 (CDK4) as a promising drug target for adrenocortical carcinoma (ACC). CDK4/6 inhibitors show potential for personalized ACC treatment, improving patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Adrenocortical carcinoma (ACC) presents a heterogeneous prognosis and limited treatment options for advanced stages.
- Identifying novel drug targets is crucial for developing personalized therapies in ACC.
Purpose of the Study:
- To identify novel drug targets for personalized treatment of adrenocortical carcinoma (ACC).
- To evaluate the potential of cyclin-dependent kinase 4 (CDK4) as a therapeutic target in ACC.
Main Methods:
- Gene expression profiling of 84 cancer drug targets in 40 ACC samples using reverse transcriptase quantitative real-time PCR.
- Investigated CDK4 protein expression in 104 ACC samples and performed in vitro experiments using ACC cell lines (NCI-H295R, MUC1).
- Tested CDK4/6 inhibitor palbociclib, alone and in combination with linsitinib, on ACC cell lines.
Main Results:
- TOP2A, IGF2, CDK1, CDK4, PLK4, and PLK1 were frequently overexpressed in ACC.
- CDK4 overexpression (62% of cases) correlated significantly with protein levels.
- Palbociclib treatment reduced ACC cell viability in a dose- and time-dependent manner, with an additive effect when combined with linsitinib.
Conclusions:
- RNA profiling effectively identifies potential drug targets in ACC.
- CDK4 is a promising actionable target for ACC treatment.
- CDK4/6 inhibitors represent a potential therapeutic strategy for selected ACC patients.
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