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Transcriptional changes associated with resistance to JQ1 treatment in MYCN-amplified neuroblastoma

ABSTRACT: 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. RNA-seq profiling of BET inhibitor resistant cells revealed that global enhancer and super-enhancer remodeling leads to differential cell state commitment and the upregulation of receptor tyrosine kinases upstream of PI3K signaling, engendering a vulnerability to receptor tyrosine kinase (RTK) and PI3K inhibition. Large-scale, unbiased, chemical combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations with JQ1, a finding validated in vivo. These studies provide a comprehensive roadmap to elucidate resistance to epigenetic-targeted cancer therapeutics and inform efficacious combination therapies for second-generation clinical trials.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107707 | GEO | 2018/12/13

REPOSITORIES: GEO

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