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

Amanda Balboni Iniguez1, Gabriela Alexe2, Emily Jue Wang1

  • 1Department 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.

Cancer Cell
|December 12, 2018
PubMed

Insights

Drug resistance to epigenetic therapies like bromodomain and extra-terminal domain (BET) inhibition can be overcome. The phosphatidylinositol 3-kinase (PI3K) pathway drives resistance, suggesting PI3K inhibitors as effective combination treatments.

Area of Science:

  • Cancer Therapeutics
  • Epigenetic Drug Resistance
  • Neuroblastoma Research

Background:

  • Drug resistance is a significant obstacle in cancer therapy, limiting treatment efficacy.
  • Mechanisms of resistance to epigenetic drugs, which target chromatin modulation, are not well understood.
  • Bromodomain and extra-terminal domain (BET) inhibitors are a class of epigenetic drugs used in cancer treatment.

Purpose of the Study:

  • To investigate resistance mechanisms to chromatin modulatory therapeutics using BET inhibition in neuroblastoma as a model.
  • To identify pathways and targets that can overcome drug resistance to epigenetic therapies.
  • To inform the development of novel combination strategies for enhanced cancer treatment.

Main Methods:

  • Utilized genome-scale, pooled lentiviral open reading frame (ORF) and CRISPR knockout rescue screens.
  • Conducted transcriptomic and chromatin profiling of resistant neuroblastoma cells.
  • Performed large-scale combinatorial screening of BET inhibitors with other therapeutic agents.

Main Results:

  • The phosphatidylinositol 3-kinase (PI3K) pathway was identified as a key mediator of resistance to BET inhibition.
  • Resistant cells exhibited global enhancer remodeling, leading to upregulation of receptor tyrosine kinases (RTKs) and PI3K signaling activation.
  • PI3K inhibitors demonstrated significant synergy when combined with BET inhibitors in upfront combinatorial screening.

Conclusions:

  • The PI3K pathway is a critical determinant of resistance to BET inhibitors in neuroblastoma.
  • Targeting the PI3K pathway, particularly through PI3K inhibitors, offers a promising strategy to overcome resistance to epigenetic therapies.
  • These findings provide a framework for understanding and combating resistance to epigenetic drugs and developing effective combination therapies.
Keywords:
BET inhibitionMYCNPI3K signalingdrug resistanceenhancer remodelingneuroblastoma

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