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

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 Nasholm; William A Weiss; Jun Qi; Rameen Beroukhim; Federica Piccioni; Cory Johannessen; Kimberly Stegmaier

doi:10.1016/j.ccell.2018.11.005

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

Cancer Cell. 2018 Dec 10;34(6):922-938.e7. doi: 10.1016/j.ccell.2018.11.005.

Authors

Amanda Balboni Iniguez¹, Gabriela Alexe², Emily Jue Wang¹, Giovanni Roti³, Sarvagna Patel⁴, Liying Chen¹, Samuel Kitara¹, Amy Conway⁵, Amanda L Robichaud⁵, Björn Stolte⁶, Pratiti Bandopadhayay¹, Amy Goodale⁷, Sasha Pantel⁷, Yenarae Lee⁷, Dorian M Cheff⁸, Matthew D Hall⁸, Rajarshi Guha⁸, Mindy I Davis⁸, Marie Menard⁹, Nicole Nasholm⁹, William A Weiss⁹, Jun Qi¹⁰, Rameen Beroukhim¹¹, Federica Piccioni⁷, Cory Johannessen⁷, Kimberly Stegmaier¹²

Affiliations

¹ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Bioinformatics Graduate Program, Boston University, Boston, MA 02215, USA.
³ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; University of Parma Department of Medicine and Surgery, Hematology and BMT, Parma, Italy.
⁴ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA 02139, USA.
⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA.
⁶ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich 80337, Germany.
⁷ The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸ National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA.
⁹ Departments of Neurology, Neurosurgery, Pediatrics, and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, USA.
¹⁰ Division of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹¹ The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹² Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: [email protected].

Abstract

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.

Keywords: BET inhibition; MYCN; PI3K signaling; drug resistance; enhancer remodeling; neuroblastoma.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Azepines / pharmacology*
Cell Line, Tumor
Disease-Free Survival
Drug Resistance, Neoplasm / drug effects*
Epigenesis, Genetic / drug effects
Female
Humans
Indazoles / pharmacology*
Mice, Nude
Molecular Targeted Therapy / methods*
Neuroblastoma / drug therapy*
Neuroblastoma / genetics
Neuroblastoma / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors
Proteins / antagonists & inhibitors
Proteins / metabolism
Signal Transduction / drug effects
Sulfonamides / pharmacology*
Triazoles / pharmacology*
Xenograft Model Antitumor Assays*

Substances

(+)-JQ1 compound
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
Azepines
Indazoles
Phosphoinositide-3 Kinase Inhibitors
Proteins
Sulfonamides
Triazoles
bromodomain and extra-terminal domain protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding