microRNA-431 as a Chemosensitizer and Potentiator of Drug Activity in Adrenocortical Carcinoma.

ABSTRACT

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine cancer with treatments limited in efficacy for metastatic disease. New molecular targeted therapies have yet to improve patient outcomes. In contrast, established treatment regimens of adrenolytics and chemotherapy have demonstrated treatment benefit, although admittedly in a minority of patients. Identification of microRNAs (miRNAs) in patients responsive to adjuvant therapy may offer a means to sensitize patients with progressive disease to existing adjuvant regimens. MATERIALS AND METHODS: Samples from primary ACC tumors of 10 Stage IV patients were examined for differentially expressed miRNAs between a "sensitive" and "resistant" cohort. Candidate microRNAs were restored via transfection in two functional ACC cell lines. Gain of function and effects on apoptosis and cell cycle were assessed. RESULTS: microRNA-431 (miR-431) was underexpressed in patients with ACC with progressive disease undergoing adjuvant therapy. Restoration of miR-431 in vitro decreased the half maximal inhibitory concentrations of doxorubicin and mitotane, with markedly increased apoptosis. We found that a reversal of epithelial-mesenchymal transition underlies the action of miR-431 with doxorubicin treatment, with Zinc Finger E-Box Binding Homeobox 1 implicated as the molecular target of miR-431 in ACC. CONCLUSION: This is the first report of the potential of miRNA therapy to sensitize ACC to current established adjuvant therapy regimens, which may mitigate the resistance underlying treatment failure in patients with advanced ACC. Effective and well-studied methods of targeted miRNA delivery in existence hints at the imminent translatability of these findings. IMPLICATIONS FOR PRACTICE Adrenocortical carcinoma (ACC) is a rare endocrine cancer with outcomes not improving despite extensive research and new targeted therapies. Mitotane and etoposide/doxorubicin/cisplatin chemotherapy is trial validated for improved recurrence-free survival. However, a minority of patients experience sustained benefit. Significant side effects exist for this regimen, with patients often unable to attain target drug doses shown to give survival benefit. This preclinical study examines the role of microRNAs in sensitizing ACC to doxorubicin or mitotane. This study offers an important bridge between new and existing cancer treatments, offering an imminently translatable approach to the treatment of adrenocortical carcinoma.