Overcoming BET Inhibitor Resistance in Malignant Peripheral Nerve Sheath Tumors

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Jonathan M CooperLu Q Le

Abstract

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. 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. Collectively, MPNST sensitivity to combination genetic and pharmacologic inhibition of BRD4 revealed the presence of a unique addicti...Continue Reading

References

Aug 2, 2001·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·M D RisJ M Boyett
May 4, 2004·Nature Reviews. Cancer·Andreas GschwindAxel Ullrich
Nov 19, 2004·Nature·Charles Sawyers
Mar 3, 2007·The Journal of Biological Chemistry·Shwu-Yuan Wu, Cheng-Ming Chiang
Sep 8, 2007·Trends in Molecular Medicine·Gang G WangPing Chi
Sep 8, 2007·Trends in Molecular Medicine·Gang G WangPing Chi
Oct 13, 2007·Science·Laura D WoodBert Vogelstein
Jun 17, 2010·The New England Journal of Medicine·Margaret A Hamburg, Francis S Collins
Sep 28, 2010·Nature·Panagis FilippakopoulosJames E Bradner
Nov 26, 2010·Nature·Cory M JohannessenLevi A Garraway
Mar 3, 2011·Nature Reviews. Clinical Oncology·Thomas TurszJean-Charles Soria
Mar 10, 2011·Nature Medicine·Manuel Rodríguez-Paredes, Manel Esteller
Aug 5, 2011·Nature·Johannes ZuberChristopher R Vakoc
Sep 6, 2011·Cell·Jake E DelmoreConstantine S Mitsiades
Dec 20, 2011·Oncogene·M Rius, F Lyko
May 16, 2012·Cancer Discovery·Levi A Garraway, Pasi A Jänne
May 26, 2012·Cancer Cell·Daniel D De CarvalhoPeter A Jones
Jul 10, 2012·Cell·Mark A Dawson, Tony Kouzarides
Sep 18, 2012·Cell·Christine Guo LianYujiang G Shi
Dec 25, 2012·Nature Cell Biology·Patricia A J Muller, Karen H Vousden
Aug 21, 2013·Cancer Research·Miguel F SeguraEva Hernando
Sep 26, 2013·Nature Reviews. Cancer·Caitriona HolohanPatrick G Johnston
Oct 26, 2013·Nature Protocols·F Ann RanFeng Zhang
Nov 29, 2013·Genes & Development·Junwei ShiChristopher R Vakoc
Dec 18, 2013·Science·Tim WangEric S Lander
Mar 4, 2014·Nature Genetics·Birgit KnoechelBradley E Bernstein
Apr 23, 2014·Nature Reviews. Drug Discovery·Panagis Filippakopoulos, Stefan Knapp

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Citations

Aug 13, 2020·Nature Reviews. Cancer·Benjamin A NacevTorsten O Nielsen
Mar 24, 2021·Nature Chemical Biology·Baishan JiangNathanael S Gray
Jul 1, 2021·Signal Transduction and Targeted Therapy·Victoria DamerellSharon Prince

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