Login to Access Video or Poster Abstract: MP37-02
Sources of Funding: NONE

Introduction

Adrenocortical carcinoma (ACC) is a rare malignancy characterized with poor survival at advanced and metastatic stage, with no curative treatment available. CTNNB1 is frequently mutated in ACC and is identified as one of the driver mutations. Current targeted therapy for CTNNB1 in ACC is lacking and our study aims to screening for effective agents with antineoplastic activity against ACC with CTNNB1 mutation._x000D_

Methods

In silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database that included drug sensitivity data of 265 compounds in 1,074 cancer cells were conducted. Drug sensitivity in cells with CTNNB1 mutation was analyzed, and further in vitro and in vivo studies were performed using the compound.

Results

Only one compound, Nutlin-3a, an MDM2 inhibitor was significantly sensitive in 18 cancer cells with CTNNB1 mutation. However, mutation of TP53, which was also common in ACC conferred significant resistance to Nutlin-3a. Further analysis of the 18 cells revealed no significant efficacy between cells with both CTNNB1 and TP53 mutation indicating concomitant TP53 mutation did not impact on drug efficacy. We verified Nutilin-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. Moreover, Nutlin-3a resulted in decreased beta-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 and hormonal secretion with no observed toxicity in mice in vivo._x000D_

Conclusions

Our study revealed Nutlin-3a, the first-generation MDM2 inhibitor potently inhibited ACC with CTNNB1 mutation. Several new derivatives of Nutlin-3a has now entered clinical trials, holding promise for targeted MDM2 inhibition in CTNNB1-mutant ACC. However, how p53/MDM2 axis coordinate with Wnt/beta-Catenin signaling in ACC warrants further study._x000D_

Funding

NONE