Enhancer remodeling promotes resistance to epigenetic-targeted therapy and engenders tumor cell vulnerabilities

Drug resistance is a major clinical challenge in achieving durable responses to targeted cancer therapeutics. Resistance mechanisms to new classes of epigenetic-targeted drugs entering the clinic remain largely unexplored. We used BET inhibition in MYCN-amplified neuroblastoma as a prototype to model innate and acquired resistance to chromatin remodeling inhibitors in cancer. Genome-scale, pooled lentiviral ORF and CRISPR knockout rescue screens nominated the PI3K pathway as a key signaling node that mediates resistance to BET inhibition. Overall design: ChIP-seq for H3K27Ac and input on JQ1 resistant and naive SK-N-BE(2)-C neuroblastoma cells engineered to overexpress either GFP control or PI3K, treated with vehicle or JQ1 for 24 hours, 1 biological replicate per condition; ChIP-seq for H3K27Ac and input on JQ1 resistant and naive Kelly neuroblastoma cells treated with vehicle or JQ1 for 24 hours, 1 biological replicate per condition; ChIP-seq for BRD4 and input on JQ1 resistant and naive SK-N-BE(2)-C neuroblastoma cells treated with vehicle or JQ1 for 24 hours, 1 biological replicate per condition.