Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer

Mol Cell. 2020 Jun 18;78(6):1096-1113.e8. doi: 10.1016/j.molcel.2020.04.027. Epub 2020 May 15.

Abstract

BET bromodomain inhibitors (BBDIs) are candidate therapeutic agents for triple-negative breast cancer (TNBC) and other cancer types, but inherent and acquired resistance to BBDIs limits their potential clinical use. Using CRISPR and small-molecule inhibitor screens combined with comprehensive molecular profiling of BBDI response and resistance, we identified synthetic lethal interactions with BBDIs and genes that, when deleted, confer resistance. We observed synergy with regulators of cell cycle progression, YAP, AXL, and SRC signaling, and chemotherapeutic agents. We also uncovered functional similarities and differences among BRD2, BRD4, and BRD7. Although deletion of BRD2 enhances sensitivity to BBDIs, BRD7 loss leads to gain of TEAD-YAP chromatin binding and luminal features associated with BBDI resistance. Single-cell RNA-seq, ATAC-seq, and cellular barcoding analysis of BBDI responses in sensitive and resistant cell lines highlight significant heterogeneity among samples and demonstrate that BBDI resistance can be pre-existing or acquired.

Keywords: ATAC-seq; BET bromodomain inhibitors; CRISPR screen; ChIP-seq; cellular barcoding; single cell ATAC-seq; single cell RNA-seq; small molecule inhibitor screen; therapeutic resistance; triple-negative breast cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Azepines / pharmacology
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Chromosomal Proteins, Non-Histone / metabolism
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Nuclear Proteins / metabolism
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism
  • Signal Transduction / drug effects
  • Transcription Factors / metabolism
  • Triazoles / pharmacology
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism

Substances

  • (+)-JQ1 compound
  • Antineoplastic Agents
  • Azepines
  • BRD2 protein, human
  • BRD4 protein, human
  • BRD7 protein, human
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Nuclear Proteins
  • Proteins
  • Transcription Factors
  • Triazoles
  • bromodomain and extra-terminal domain protein, human