Targeted Gene Expression Profile Reveals CDK4 as Therapeutic Target for Selected Patients With Adrenocortical Carcinoma.
- Liang R Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital of Wuerzburg, Würzburg, Germany.
- Weigand I Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital of Wuerzburg, Würzburg, Germany.
- Lippert J Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital of Wuerzburg, Würzburg, Germany.
- Kircher S Institute of Pathology, University of Wuerzburg, Würzburg, Germany.
- Altieri B Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital of Wuerzburg, Würzburg, Germany.
- Steinhauer S Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital of Wuerzburg, Würzburg, Germany.
- Hantel C Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland.
- Rost S Institute of Human Genetics, University of Wuerzburg, Würzburg, Germany.
- Rosenwald A Institute of Pathology, University of Wuerzburg, Würzburg, Germany.
- Kroiss M Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital of Wuerzburg, Würzburg, Germany.
- Fassnacht M Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital of Wuerzburg, Würzburg, Germany.
- Sbiera S Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital of Wuerzburg, Würzburg, Germany.
- Ronchi CL Division of Endocrinology and Diabetology, Department of Internal Medicine, University Hospital of Wuerzburg, Würzburg, Germany.
- 2020-05-07
Published in:
- Frontiers in endocrinology. - 2020
English
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.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.3389/fendo.2020.00219
- PMID 32373071
- Persistent URL
- https://sonar.ch/global/documents/298787
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