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Cancer Cell DOI:10.1016/j.ccell.2018.11.005

Resistance to Epigenetic-Targeted Therapy Engenders Tumor Cell Vulnerabilities Associated with Enhancer Remodeling.

Publication TypeJournal Article
Year of Publication2018
AuthorsIniguez, ABalboni, Alexe, G, Wang, EJue, Roti, G, Patel, S, Chen, L, Kitara, S, Conway, A, Robichaud, AL, Stolte, B, Bandopadhayay, P, Goodale, A, Pantel, S, Lee, Y, Cheff, DM, Hall, MD, Guha, R, Davis, MI, Menard, M, Nasholm, N, Weiss, WA, Qi, J, Beroukhim, R, Piccioni, F, Johannessen, C, Stegmaier, K
JournalCancer Cell
Date Published2018 Dec 10

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.


Alternate JournalCancer Cell
PubMed ID30537514
PubMed Central IDPMC6352909
Grant ListP01 CA217959 / CA / NCI NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
R01 CA188228 / CA / NCI NIH HHS / United States
R01 NS088355 / NS / NINDS NIH HHS / United States