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

Publication date: 10 December 2018Source: Cancer Cell, Volume 34, Issue 6Author(s): Amanda Balboni Iniguez, Gabriela Alexe, Emily Jue Wang, Giovanni Roti, Sarvagna Patel, Liying Chen, Samuel Kitara, Amy Conway, Amanda L. Robichaud, Björn Stolte, Pratiti Bandopadhayay, Amy Goodale, Sasha Pantel, Yenarae Lee, Dorian M. Cheff, Matthew D. Hall, Rajarshi Guha, Mindy I. Davis, Marie Menard, Nicole NasholmSummaryDrug 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research