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

Shaokun Shu1, Hua-Jun Wu2, Jennifer Y Ge3

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Molecular Cell
|May 17, 2020
PubMed

Insights

BET bromodomain inhibitors show promise for triple-negative breast cancer, but resistance is a challenge. This study identifies genetic vulnerabilities and resistance mechanisms, offering new therapeutic strategies for overcoming resistance to these cancer drugs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • BET bromodomain inhibitors (BBDIs) are investigated as therapeutics for triple-negative breast cancer (TNBC).
  • Inherent and acquired resistance to BBDIs hinders their clinical application.
  • Understanding resistance mechanisms is crucial for effective cancer therapy.

Purpose of the Study:

  • To identify synthetic lethal interactions with BBDIs.
  • To uncover genes conferring resistance to BBDIs.
  • To elucidate functional differences among BRD2, BRD4, and BRD7 in BBDI response.

Main Methods:

  • CRISPR and small-molecule inhibitor screens were employed.
  • Comprehensive molecular profiling of BBDI response and resistance was performed.
  • Single-cell RNA-seq, ATAC-seq, and cellular barcoding analyzed BBDI effects.

Main Results:

  • Synergistic interactions were observed with cell cycle regulators, YAP, AXL, SRC signaling, and chemotherapy.
  • BRD2 deletion sensitized cells to BBDIs, while BRD7 loss promoted resistance via TEAD-YAP.
  • Significant heterogeneity in BBDI response and pre-existing/acquired resistance were highlighted.

Conclusions:

  • Genetic vulnerabilities and resistance mechanisms to BBDIs in TNBC were identified.
  • Targeting synthetic lethal interactions and understanding BRD protein functions can overcome BBDI resistance.
  • BBDI resistance is complex, involving pre-existing and acquired mechanisms and cellular heterogeneity.
Keywords:
ATAC-seqBET bromodomain inhibitorsCRISPR screenChIP-seqcellular barcodingsingle cell ATAC-seqsingle cell RNA-seqsmall molecule inhibitor screentherapeutic resistancetriple-negative breast cancer

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