Targeted gene expression profile reveals CDK4 as therapeutic target for selected patients with adrenocortical carcinoma

Research output: Contribution to journalArticlepeer-review

Authors

  • Raimunde Liang
  • Isabel Weigand
  • Juliane Lippert
  • Stefan Kircher
  • Barbara Altieri
  • Sonja Steinhauer
  • Constanze Hantel
  • Simone Rost
  • Andreas Rosenwald
  • Matthias Kroiss
  • Martin Fassnacht
  • Silviu Sbiera

Colleges, School and Institutes

External organisations

  • University of Wuerzburg
  • University of Wurzburg

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.

Details

Original languageEnglish
Article number219
Number of pages13
JournalFrontiers in Endocrinology
Volume11
Publication statusPublished - 16 Apr 2020

Keywords

  • adrenocortical tumor, targeted therapy, palbociclib, CDK4, IGF1R

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