Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling.
Drug resistance represents a major challenge to achieving durable responses to cancer therapeutics. Resistance mechanisms to epigenetically targeted drugs remain largely unexplored. We used bromodomain and extra-terminal domain (BET) inhibition in neuroblastoma as a prototype to model resistance to chromatin modulatory therapeutics. Genome-scale, pooled lentiviral open reading frame (ORF) and CRISPR knockout rescue screens nominated the phosphatidylinositol 3-kinase (PI3K) pathway as promoting resistance to BET inhibition. Transcriptomic and chromatin profiling of resistant cells revealed that global enhancer remodeling is associated with upregulation of receptor tyrosine kinases (RTKs), activation of PI3K signaling, and vulnerability to RTK/PI3K inhibition. Large-scale combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations. These studies provide a roadmap to elucidate resistance to epigenetic-targeted therapeutics and inform efficacious combination therapies.
|Year of Publication||
2018 12 10
|PubMed Central ID||
R01 CA188228 / CA / NCI NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
P50 CA206963 / CA / NCI NIH HHS / United States
R01 NS088355 / NS / NINDS NIH HHS / United States
P01 CA217959 / CA / NCI NIH HHS / United States
R35 CA210030 / CA / NCI NIH HHS / United States
R01 CA222218 / CA / NCI NIH HHS / United States
P01 CA142106 / CA / NCI NIH HHS / United States