Overcoming BET Inhibitor Resistance in Malignant Peripheral Nerve Sheath Tumors

©2019 American Association for Cancer Research..

PURPOSE: BET bromodomain inhibitors have emerged as a promising therapy for numerous cancer types in preclinical studies, including neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumor (MPNST). However, potential mechanisms underlying resistance to these inhibitors in different cancers are not completely understood. In this study, we explore new strategy to overcome BET inhibitor resistance in MPNST.Experimental Design: Through modeling tumor evolution by studying genetic changes underlying the development of MPNST, a lethal sarcoma with no effective medical treatment, we identified a targetable addiction to BET bromodomain family member BRD4 in MPNST. This served as a controlled model system to delineate mechanisms of sensitivity and resistance to BET bromodomain inhibitors in this disease.

RESULTS: Here, we show that a malignant progression-associated increase in BRD4 protein levels corresponds to partial sensitivity to BET inhibition in MPNST. Strikingly, genetic depletion of BRD4 protein levels synergistically sensitized MPNST cells to diverse BET inhibitors in culture and in vivo.

CONCLUSIONS: Collectively, MPNST sensitivity to combination genetic and pharmacologic inhibition of BRD4 revealed the presence of a unique addiction to BRD4 in MPNST. Our discovery that a synthetic lethality exists between BET inhibition and reduced BRD4 protein levels nominates MPNST for the investigation of emerging therapeutic interventions such as proteolysis-targeting chimeras (PROTACs) that simultaneously target bromodomain activity and BET protein abundance.

Medienart:

E-Artikel

Erscheinungsjahr:

2019

Erschienen:

2019

Enthalten in:

Zur Gesamtaufnahme - volume:25

Enthalten in:

Clinical cancer research : an official journal of the American Association for Cancer Research - 25(2019), 11 vom: 01. Juni, Seite 3404-3416

Sprache:

Englisch

Beteiligte Personen:

Cooper, Jonathan M [VerfasserIn]
Patel, Amish J [VerfasserIn]
Chen, Zhiguo [VerfasserIn]
Liao, Chung-Ping [VerfasserIn]
Chen, Kun [VerfasserIn]
Mo, Juan [VerfasserIn]
Wang, Yong [VerfasserIn]
Le, Lu Q [VerfasserIn]

Links:

Volltext

Themen:

Antineoplastic Agents
BRD4 protein, human
Bromodomain and extra-terminal domain protein, human
Cell Cycle Proteins
Journal Article
Proteins
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Transcription Factors

Anmerkungen:

Date Completed 06.07.2020

Date Revised 06.07.2020

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1158/1078-0432.CCR-18-2437

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM29420976X