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Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■肾上腺皮质癌（ACC）是一种侵袭性内分泌恶性肿瘤，治疗选择有限。用米托坦治疗高级ACC，基石疗法，仍然具有挑战性，因此强调了在治疗前预测米托坦反应和寻求其他有效治疗策略的重要性。
■我们旨在通过使用患者来源的ACC细胞（PDC）的体外测定来确定米托坦的功效，确定与米托坦反应相关的分子生物标志物，并初步探索ACC的潜在药物。
■在17个PDC中进行了体外米托坦敏感性测试，并在8个PDC中进行了针对40种化合物的高通量筛选。使用外显子组和转录组测序在9个样品中评估遗传特征。
■PDCs表现出对米托坦治疗的不同敏感性。应答者（n=8）和非应答者（n=9）的中位细胞活力抑制率为48.4％（IQR：39.3-59.3％）和-1.2％（IQR：-26.4-22.1％），分别。应答者的IC50和AUC中位数显着降低（IC50：53.4µM对74.7µM，P<0.0001;AUC:158.0vs213.5,P<0.0001)。基因组分析显示CTNNB1体细胞改变仅在应答者中发现(3/5),而ZNRF3改变仅在非应答者中发现(3/4)。转录组学分析发现，与脂质代谢相关的途径在应答者肿瘤中上调，而CYP27A1和ABCA1表达与体外米托坦敏感性呈正相关。此外，药理学分析确定包括双硫仑在内的化合物，氯硝柳胺和硼替佐米对PDCs有疗效.
■ACCPDC可用于测试药物反应，药物再利用和指导个性化治疗。我们的结果表明，对米托坦的反应可能与对脂质代谢的依赖性有关。CYP27A1和ABCA1表达可能是米托坦反应的预测标志物，和双硫仑，氯硝柳胺和硼替佐米可能是潜在的治疗药物，两者都需要进一步调查。
■我们旨在通过使用患者来源的ACC细胞（PDC）的体外测定来确定米托坦的功效，确定与米托坦反应相关的分子生物标志物，并初步探索ACC的潜在药物。
■在17个PDC中进行了体外米托坦敏感性测试，并在8个PDC中进行了针对40种化合物的高通量筛选。使用外显子组和转录组测序在9个样品中评估遗传特征。
■PDCs表现出对米托坦治疗的不同敏感性。应答者（n=8）和非应答者（n=9）的中位细胞活力抑制率为48.4％（IQR：39.3-59.3％）和-1.2％（IQR：-26.4-22.1％），分别。应答者的IC50和AUC中位数显着降低（IC50：53.4µM对74.7µM，P<0.0001;AUC:158.0vs213.5,P<0.0001)。基因组分析显示CTNNB1体细胞改变仅在应答者中发现(3/5),而ZNRF3改变仅在非应答者中发现(3/4)。转录组学分析发现，与脂质代谢相关的途径在应答者肿瘤中上调，而CYP27A1和ABCA1表达与体外米托坦敏感性呈正相关。此外，药理学分析确定包括双硫仑在内的化合物，氯硝柳胺和硼替佐米对PDCs有疗效.
■ACCPDC可用于测试药物反应，药物再利用和指导个性化治疗。我们的结果表明，对米托坦的反应可能与对脂质代谢的依赖性有关。CYP27A1和ABCA1表达可能是米托坦反应的预测标志物，和双硫仑，氯硝柳胺和硼替佐米可能是潜在的治疗药物，两者都需要进一步调查。
