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The HDAC3–SMARCA4–miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma

The HDAC inhibitor entinostat sensitizes a subset of rhabdomyosarcomas to chemotherapy. Targeted treatment for pediatric aRMS Rhabodomyosarcoma is a soft tissue tumor in children that is difficult to treat. A chromosomal abnormality generates a fusion protein called PAX3:FOXO1 that drives chemoresistance and aggressive progression in patients with the alveolar subtype of the disease (aRMS). Early-phase clinical trials have shown tolerability of the histone deacetylase (HDAC) inhibitor entinostat in pediatric patients. Here, using cells and animal models, Bharathy et al. found that entinostat works in aRMS by specifically blocking the activity of HDAC3, thereby preventing epigenetic suppression of a microRNA that inhibits PAX3:FOXO1 translation. Without PAX3:FOXO1 protein, aRMS growth slowed, and tumors were sensitized to the chemotherapy vincristine. These findings and ongoing clinical trials show promise for an effective therapy for some patients with aRMS. Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. We previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I–specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, we established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance. HDAC3 inhibition by entinostat decreased the activity of the chromatin remodeling enzyme SMARCA4, which, in turn, derepressed the microRNA miR-27a. This reexpression of miR-27a led to PAX3:FOXO1 mRNA destabilization and chemotherapy sensitization in aRMS cells in culture and in vivo. Furthermore, a phase 1 clinical trial (ADVL1513) has shown that entinostat is tolerable in children with relapsed or refractory solid tumors and is planned for phase 1B cohort expansion or phase 2 clinical trials. Together, these results implicate an HDAC3–SMARCA4–miR-27a–PAX3:FOXO1 circuit as a driver of chemoresistant aRMS and suggest that targeting this pathway with entinostat may be therapeutically effective in patients.