ECE2023 Oral Communications Oral Communications 6: Endocrine-related Cancer (6 abstracts)
WEE1 kinase inhibitor, adavosertib (AZD1775), as a novel potential therapeutic strategy in advanced adrenocortical carcinoma
Mariangela Tamburello 1 , Silviu Sbiera 1 , Weber Justus 2 , Juliane Lippert 1 , Mario Detomas 1 , Marc Philipp Schauer 1,2 , Hanna Urlaub 1 , Sonja Steinhauer 1 , Otilia Kimpel 1 , Laura-Sophie Landwehr 1 , Hantel Constanze 3,4 , Sandra Sigala 5 , Cristina Ronchi 1,6 , Michael Hudecek 2 , Kiseljak-Vassiliades Katja 7 , Martin Fassnacht 1 & Barbara Altieri 1
1University Hospital Würzburg, Division of Endocrinology and
Diabetes, Department of Internal Medicine I, Würzburg, Germany; 2Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II,, Würzburg, Germany; 3University Hospital of Zürich; 3Department of Endocrinology, Diabetology and Clinical Nutrition, Zürich, Switzerland; 4University Hospital Carl Gustav Carus Dresden, Medizinische Klinik und Poliklinik III, Dresden, Germany; 5University of Brescia, Department of Molecular and Translational Medicine, Brescia, Italy; 6University of Birmingham, Institute of Metabolism and System Research, United Kingdom; 7University of Colorado Anschutz Medical Campus, Aurora, United States
Background: Adrenocortical cancer (ACC) is a rare malignant neoplasm with a dismal prognosis, particularly in advanced disease. For these patients only limited therapeutic options are available. Adavosertib (AZD1775) is a potent inhibitor of tyrosine kinase WEE1 that regulates cell cycle checkpoints, slowing cell cycle progression and leading to mitotic entry in the presence of DNA damage. Therefore, its use could potentiate existing DNA damage-based therapies. Here, we evaluate the expression of WEE1 in ACC tissues and ACC cell lines and investigate the effect of adavosertib alone or in combination with cisplatin or gemcitabine in vitro.
Methods: WEE1 mRNA expression has been evaluated in 91 adrenocortical tissues (19 normal adrenal glands/NAG; 20 adenomas/ACA; 52 ACC) and 5 available ACC cell lines. Immunohistochemistry was assessed in 114 paraffin-embedded ACC tissues (with known TP53 mutation status) and evaluated by automated image analysis. WEE1 expression was correlated with clinical outcome. In vitro cell viability was evaluated by CellTiter-Glo assay following exposure of cells for 96h to increasing concentrations of adavosertib alone or in combination with cisplatin or gemcitabine according to the Chou and Talalay method. Cell apoptosis and cell cycle were analyzed by flow cytometry.
Results: WEE1 levels were significantly higher in ACC compared to NAG (0.032 vs 0.012, respectively, P=0.04) but not to ACA. Low WEE1 mRNA levels were associated with better overall survival (HR 0.32, 95% CI 0.12-0.86, P=0.02), independently of established prognostic factors, whereas only a trend was observed at protein level (HR 0.31, 95% CI 0.07-1.26, P=0.10). WEE1 staining was significantly higher in TP53 mutated ACC (n=34) compared to wild type (n=80; median score 97 vs 72, P<0.001). Exposure of NCI-H295R, JIL-2266 and CU-ACC2 cells to adavosertib induced cytotoxicity with IC50 of 1.17, 1.35 and 0.4 µM, respectively. CU-ACC1 and MUC-1 showed less sensitivity to adavosertib alone, but its effect was enhanced by cisplatin and gemcitabine and this additive-synergic effect was observed in all cell lines. Upon 48h of treatment with adavosertib alone (1.25 μM), all cell lines showed an increased frequency of dead cells and apoptotic cells with enrichment of cells in the S phase, compared to the DMSO control.
Conclusion: Our results showed high WEE1 expression in ACC tissue and cell lines. WEE1-inhibitor adavosertib exerts a cytotoxic effect on ACC cells inducing apoptosis and cell cycle perturbation. Cisplatin and gemcitabine, commonly used in ACC treatment, enhanced the adavosertib effect, giving a new pharmacological option in ACC over standard therapies.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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