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Published on: July 25, 2020
Pharmacogenomic analysis in adrenocortical carcinoma reveals genetic features associated with mitotane sensitivity
Jie Zhang1, Luming Wu1, Tingwei Su1
1Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background:
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.
Objective:
We aimed to determine the efficacy of mitotane via an in vitro assay using patient-derived ACC cells (PDCs), identify molecular biomarkers associated with mitotane response and preliminarily explore potential agents for ACC.
Methods:
In vitro 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.
Results:
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<0.0001; AUC: 158.0 vs 213.5, P<0.0001). Genomic analysis revealed CTNNB1 somatic alterations were only found in responders (3/5) while ZNRF3 alterations only in non-responders (3/4). Transcriptomic profiling found pathways associated with lipid metabolism were upregulated in responder tumors whilst CYP27A1 and ABCA1 expression were positively correlated to in vitro mitotane sensitivity. Furthermore, pharmacologic analysis identified that compounds including disulfiram, niclosamide and bortezomib exhibited efficacy against PDCs.
Conclusion:
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. CYP27A1 and ABCA1 expression could be predictive markers for mitotane response, and disulfiram, niclosamide and bortezomib could be potential therapeutics, both warranting further investigation.
Insights
Patient-derived adrenocortical carcinoma cells show variable response to mitotane. Lipid metabolism pathways and specific gene expressions like CYP27A1 and ABCA1 may predict treatment success, suggesting new therapeutic avenues.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Adrenocortical carcinoma (ACC) is an aggressive endocrine cancer with limited treatment options.
- Mitotane is the standard therapy for advanced ACC, but its effectiveness is challenging to predict.
- Predicting mitotane response and identifying alternative therapies are crucial for improving patient outcomes.
Purpose of the Study:
- To evaluate the efficacy of mitotane using patient-derived ACC cells (PDCs) in vitro.
- To identify molecular biomarkers associated with mitotane response in ACC.
- To explore potential new therapeutic agents for ACC.
Main Methods:
- In vitro mitotane sensitivity testing was performed on 17 PDCs.
- High-throughput screening of 40 compounds was conducted on 8 PDCs.
- Exomic and transcriptomic sequencing were used to analyze genetic features in 9 samples.
Main Results:
- PDCs displayed variable sensitivity to mitotane, with responders showing significantly lower IC50 and AUC values.
- Genomic analysis revealed CTNNB1 alterations in responders and ZNRF3 alterations in non-responders.
- Lipid metabolism pathways were upregulated in responders, and CYP27A1 and ABCA1 expression correlated with mitotane sensitivity. Disulfiram, niclosamide, and bortezomib showed efficacy against PDCs.
Conclusions:
- ACC PDCs are valuable for drug response testing, drug repurposing, and guiding personalized therapy.
- Mitotane response may be linked to lipid metabolism dependency.
- CYP27A1, ABCA1, disulfiram, niclosamide, and bortezomib warrant further investigation as predictive markers and potential therapeutics.
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