Abstract
Adrenocortical carcinoma (ACC) is a rare malignancy, and CTNNB1 is frequently mutated in ACC. Our study aims to screen for effective agents with antineoplastic activity against ACC with CTNNB1 mutation. In‐silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database was conducted. Drug sensitivity in cells with CTNNB1 mutation was analyzed and further in vitro and in vivo studies were performed using the compound. Only one compound, Nutlin‐3a, an MDM2 inhibitor, was significantly sensitive in 18 cancer cells with CTNNB1 mutation. Further analysis of the 18 cells revealed no significant efficacy between cells with both CTNNB1 and TP53 mutations indicating concomitant TP53 mutation did not impact on drug efficacy. We verified that Nutlin‐3a inhibited cellular proliferation in ACC cell line NCI‐H295R which harbored CTNNB1 mutation but not in SW13 cells which did not. Nutlin‐3a induced cell apoptosis and G1 cell‐cycle arrest in NCI‐H295R cells. Nutlin‐3a also decreased cellular migration and inhibited epithelial‐to‐mesenchymal transition (EMT) process in terms of EMT index. Nutlin‐3a resulted in decreased β‐catenin level independent of p53 level in NCI‐H295R but not SW13 cells. We also evaluated the effect of Nutlin‐3a on hormonal secretion of NCI‐H295R cells and found it resulted in decreased levels of cortisol, androgen, and progesterone. Nutlin‐3a treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Our study has revealed that Nutlin‐3a potently inhibits ACC with CTNNB1 mutation. How p53/MDM2 axis coordinates with Wnt/beta‐Catenin signaling in ACC warrants further study.
Highlights
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an annual incidence ranging from one to two case per million people [1]
As adrenocortical carcinoma is remarkable for its excessive hormone-producing ability, we analyzed the characteristics of hormone secretion based on TCGA ACC dataset
As Wnt pathway activation was critical in ACC tumorigenesis, CTNNB1 overexpression and its association with hormone was analyzed
Summary
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an annual incidence ranging from one to two case per million people [1]. Clinical stage classification proposed by the European Network for the Study of Adrenal Tumors (ENSAT) is recommended as staging remains the most solid prognostic parameter [2]. The ENSAT stage, unlike conventional staging systems that solely encompass tumor extension, includes hormonal workup as a whole. According to ENSAT guideline, complete surgical resection is the only curative method to treat ACC and management of hormonal excess is majorly dependent on adrenolytic agents. Most of the cases are locally invasive or have metastasized to distant organs at the time of diagnosis. For advanced ACC, combination of cytotoxic drugs and mitotane was the recommended but the poor therapeutic efficiency and severe side effects limit clinical utility [3]. Developing new agents to improve the therapeutic effects is urgent
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