Nutlin-3a as a novel anticancer agent for adrenocortical carcinoma with CTNNB1 mutation

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.