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Overcoming BET Inhibitor Resistance in Malignant Peripheral Nerve Sheath Tumors

Jonathan M Cooper1, Amish J Patel1,2, Zhiguo Chen1

  • 1Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|February 24, 2019
PubMed
Abstract

Insights

Neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors (MPNST) show addiction to BRD4. Reducing BRD4 levels synergistically enhances sensitivity to BET inhibitors, offering a new therapeutic strategy for MPNST.

Area of Science:

  • Oncology
  • Cancer Biology
  • Pharmacology

Background:

  • BET bromodomain inhibitors show promise for various cancers, including NF1-associated MPNST.
  • Mechanisms of resistance to BET inhibitors are not fully understood.
  • MPNST is a lethal sarcoma lacking effective medical treatments.

Purpose of the Study:

  • To explore strategies for overcoming BET inhibitor resistance in MPNST.
  • To identify targetable dependencies in MPNST development and progression.
  • To delineate mechanisms of sensitivity and resistance to BET inhibitors in MPNST.

Main Methods:

  • Modeling tumor evolution and genetic changes in MPNST.
  • Investigating the role of BRD4 in MPNST sensitivity and resistance.
  • Utilizing genetic depletion and pharmacologic inhibition of BRD4.
  • Evaluating BET inhibitor efficacy in vitro and in vivo.

Main Results:

  • MPNST exhibits a malignant progression-associated increase in BRD4 protein levels.
  • Genetic depletion of BRD4 synergistically sensitizes MPNST cells to BET inhibitors.
  • This sensitization was observed both in cell culture and in vivo.

Conclusions:

  • MPNST demonstrates a unique addiction to BRD4.
  • A synthetic lethality exists between BET inhibition and reduced BRD4 protein levels.
  • This finding supports the investigation of therapeutics like PROTACs for MPNST.

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