ECE2019 Oral Communications Adrenal 2 (5 abstracts)
Cyclin dependent kinase 4 as promising drug target in adrenocortical carcinoma
Raimunde Liang 1 , Isabel Weigand 1 , Silviu Sbiera 1 , Stefan Kircher 2 , Juliane Lippert 2 , Barbara Altieri 1 , Sonja Steinhauer 1 , Constanze Hantel 3, , Simone Rost 2 , Andreas Rosenwald 2 , Matthias Kroiss 1 , Martin Fassnacht 1 & Cristina Ronchi 1,
1University Hospital of Wuerzburg, Wuerzburg, Germany; 2University of Wuerzburg, Wuerzburg, Germany; 3University Hospital of Zurich, Zurich, Switzerland; 4University Hospital Carl Gustav Carus Dresden, Dresden, Germany; 5University of Birmingham, Birmingham, UK.
Adrenocortical carcinomas (ACC) are associated with heterogeneous prognosis and limited treatment options for advanced stages. Until now no efficient targeted therapies have been identified. This study aims to identify possible new molecular drug targets for a future personalized therapeutic approach. RNA was isolated from 40 formalin-fixed paraffin-embedded tumor samples from ACC patients (26F&14M, median age 46 yrs) with known genetic background (Lippert et al. JCEM 2018). Gene expression of 84 known cancer drug targets was evaluated by RT2 Profiler PCR Array (Qiagen) and fold change (FC) was calculated with the 2^(-ΔΔCT) formula using 5 normal adrenal glands (NAG) as reference. Most frequently overexpressed genes were TOP2A (100% of cases, median FC=16.5), IGF2 (95%, FC=52.9), CDK1 (80%, FC=6.7), CDK4 (62%, FC=2.9), PLK4 (60%, FC=2.8) and PLK1 (52%, FC=2.3). CDK4 was chosen as the most promising candidate for functional validation as actionable by approved CDK4/6 inhibitors. ACC samples with copy number gains at CDK4 locus (n=24) presented significantly higher CDK4 expression levels (P=0.0023). Nuclear CDK4 protein expression was investigated by immunohistochemistry and significantly correlated with mRNA expression (R=0.52, P<0.005). Efficacy of CDK4/6 inhibitor palbociclib (0.5–16 μM) was tested in vitro using two adrenocortical carcinoma cell lines (NCI-H295R and MUC1). We found a concentration- and time-dependent reduction of cell viability, which was more pronounced in NCI-H295R in line with higher CDK4 expression at western blot analysis. Furthermore, we tested palbociclib in combination with dual IGFR/IR inhibitor linsitinib (0.125–4 μM) and showed a synergistic effect on inhibiting cell viability. In conclusion, in this proof-of-principle study we confirm that RNA profiling is useful to discover potential drug targets that could be then investigated by immunohistochemistry in the clinical practice. CDK4/6 inhibitors are promising candidates for treatment of a subset of patients with adrenocortical carcinoma.
Volume 63
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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