Therapeutically targeting oncogenic CRCs facilitates induced differentiation of NB by RA and the BET bromodomain inhibitor

Abstract

Retinoic acids (RAs) are the most successful therapeutics for cancer differentiation therapy used in high-risk neuroblastoma (NB) maintenance therapy but are limited in effectiveness. This study identifies a strategy for improving efficacy through disruption of cancer cell identity via BET inhibitors. Mutations that block development are theorized to cause NB through retention of immature cell identities contributing to oncogenesis. NB has two interchangeable cell identities, maintained by two different core transcriptional regulatory circuitries (CRCs): a therapy-resistant mesenchymal/stem cell state and a proliferative adrenergic cell state. MYCN amplification is a common mutation of high-risk NB and recently found to block differentiation by driving high expression of the adrenergic CRC transcription factor ASCL1. We investigated whether disruption of immature CRCs can promote RA-induced differentiation since only a subset of NB patients responds to RA. We found that silencing ASCL1, a critical member of the adrenergic CRC, or global disruption of CRCs with the BET inhibitor JQ1, suppresses gene expression of multiple CRC factors, improving RA-mediated differentiation. Further, JQ1 and RA synergistically decrease proliferation and induce differentiation in NB cell lines. Our findings support preclinical studies of RA and BET inhibitors as a combination therapy in treating NB.