AUTHOR=Zhang Jie , Wu Luming , Su Tingwei , Liu Haoyu , Jiang Lei , Jiang Yiran , Wu Zhiyuan , Chen Lu , Li Haorong , Zheng Jie , Sun Yingkai , Peng Hangya , Han Rulai , Ning Guang , Ye Lei , Wang Weiqing 

TITLE=Pharmacogenomic analysis in adrenocortical carcinoma reveals genetic features associated with mitotane sensitivity and potential therapeutics

JOURNAL=Frontiers in Endocrinology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1365321

DOI=10.3389/fendo.2024.1365321

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>Adrenocortical carcinoma (ACC) is an aggressive endocrine malignancy with limited therapeutic options. Treating advanced ACC with mitotane, the cornerstone therapy, remains challenging, thus underscoring the significance to predict mitotane response prior to treatment and seek other effective therapeutic strategies.</p></sec><sec><title>Objective</title><p>We aimed to determine the efficacy of mitotane via an <italic>in vitro</italic> assay using patient-derived ACC cells (PDCs), identify molecular biomarkers associated with mitotane response and preliminarily explore potential agents for ACC.</p></sec><sec><title>Methods</title><p><italic>In vitro</italic> mitotane sensitivity testing was performed in 17 PDCs and high-throughput screening against 40 compounds was conducted in 8 PDCs. Genetic features were evaluated in 9 samples using exomic and transcriptomic sequencing.</p></sec><sec><title>Results</title><p>PDCs exhibited variable sensitivity to mitotane treatment. The median cell viability inhibition rate was 48.4% (IQR: 39.3-59.3%) and -1.2% (IQR: -26.4-22.1%) in responders (n=8) and non-responders (n=9), respectively. Median IC50 and AUC were remarkably lower in responders (IC50: 53.4 µM vs 74.7 µM, P&lt;0.0001; AUC: 158.0 vs 213.5, P&lt;0.0001). Genomic analysis revealed <italic>CTNNB1</italic> somatic alterations were only found in responders (3/5) while <italic>ZNRF3</italic> alterations only in non-responders (3/4). Transcriptomic profiling found pathways associated with lipid metabolism were upregulated in responder tumors whilst <italic>CYP27A1</italic> and <italic>ABCA1</italic> expression were positively correlated to <italic>in vitro</italic> mitotane sensitivity. Furthermore, pharmacologic analysis identified that compounds including disulfiram, niclosamide and bortezomib exhibited efficacy against PDCs.</p></sec><sec><title>Conclusion</title><p>ACC PDCs could be useful for testing drug response, drug repurposing and guiding personalized therapies. Our results suggested response to mitotane might be associated with the dependency on lipid metabolism. <italic>CYP27A1</italic> and <italic>ABCA1</italic> expression could be predictive markers for mitotane response, and disulfiram, niclosamide and bortezomib could be potential therapeutics, both warranting further investigation.</p></sec>