BET inhibitors(The University of Nottingham)

NF2-related schwannomatosis (NF2-SWN) is a genetic predisposition to develop multiple schwannomas that cause serious neurological disabilities for which there are no approved drug therapies. We previously reported that the MEK inhibitor trametinib slowed schwannoma growth in two mouse models, however, ERK reactivation was observed. Pathway analysis of the proteome of trametinib-treated mouse schwannoma model cells predicted activation of BRD4. To elucidate the adaptive mechanisms contributing to cell survival, we studied the trametinib response in novel immortalized and non-immortalized human schwannoma model cells (MD-HSCs). MD-HSCs exposed to trametinib avoid cell death by upregulating expression of ECM and cell adhesion proteins resulting in an increase in cell size, stress fiber formation, and a switch from c-Jun to Krox20/Egr2 nuclear expression. We demonstrate that BET proteins mediate the survival response to trametinib in MD-HSCs. Preventing this epigenetic adaptation to trametinib with BET inhibitors induces schwannoma cell death. However, this response is not observed when BET inhibitors are combined with brigatinib, a multi-kinase inhibitor in clinical use. These findings highlight the complex cellular adaptations in schwannomas and suggest that targeting BET alongside MEK inhibition prevents resistance mechanisms and promotes cell death.