Bromodomain Inhibitors to Prevent Development of Resistance to Targeted Kinase Inhibitors in Schwannomas [ChIP-seq]

We identified a BRD4 and a PAK inhibitor that acted in concert to selectively slow growth of a human schwannoma line compared to its merlin-expressing parental line. BRD4 is a member of the BET family of bromodomain containing proteins that bind acetylated lysine in transcription regulatory proteins to alter gene expression. BRD proteins contribute to development of resistance to cancer drugs.

Follow-up studies confirmed the drugs’ interaction in multiple mouse and human schwannoma lines. We will extend this research by assessing the ability of BRD4 inhibitors in combination with multiple PAK, PI3K, MEK, and FAK inhibitors, some of which are in NF2 clinical trials (selumetinib, crizotinib, brigatinib, trametinib) to reduce the viability of schwannoma lines. We will measure whether the combinations provide long-lasting inhibition of cell proliferation, induce cell death, and block compensatory escape pathways that often arise when cells are treated with a single kinase inhibitor.

We will use an established mouse xenograft model to test the effectiveness of the best performing in vitro drug combination. Mechanisms of action studies will complete the preclinical evaluation of the advanced drug combination in a representative cell line. Our proposed study is timely because the results will indicate whether drug resistance could develop for several of the kinase inhibitors in ongoing NF2 clinical trials.

Moreover, the results could indicate whether BRD4 inhibitors could serve as an adjuvant therapy to prevent drug resistance. By assessing the RNAome and methylome of single and dual treated human schwannoma cells, we will uncover the genes and RNAs that undergo BRD4-dependent epigenetic regulation to trigger compensatory pathways. With further validation, these candidate genes and RNAs may serve as biomarkers for treatment response and/or resistance development.

Thus, these preclinical studies are at the forefront of addressing questions critical to ongoing efforts to develop a pharmacotherapy for NF2 schwannomas.