PMID- 30885979
OWN - NLM
STAT- In-Data-Review
LR  - 20190610
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 79
IP  - 9
DP  - 2019 May 1
TI  - Inhibition of NF-kappaB-Dependent Signaling Enhances Sensitivity and Overcomes
      Resistance to BET Inhibition in Uveal Melanoma.
PG  - 2415-2425
LID - 10.1158/0008-5472.CAN-18-3177 [doi]
AB  - Bromodomain and extraterminal protein inhibitors (BETi) are epigenetic therapies 
      aimed to target dysregulated gene expression in cancer cells. Despite early
      successes of BETi in a range of malignancies, the development of drug resistance 
      may limit their clinical application. Here, we evaluated the mechanisms of BETi
      resistance in uveal melanoma, a disease with little treatment options, using two 
      approaches: a high-throughput combinatorial drug screen with the clinical BET
      inhibitor PLX51107 and RNA sequencing of BETi-resistant cells. NF-kappaB
      inhibitors synergistically sensitized uveal melanoma cells to PLX51107 treatment.
      Furthermore, genes involved in NF-kappaB signaling were upregulated in
      BETi-resistant cells, and the transcription factor CEBPD contributed to the
      mechanism of resistance. These findings suggest that inhibitors of NF-kappaB
      signaling may improve the efficacy of BET inhibition in patients with advanced
      uveal melanoma. SIGNIFICANCE: These findings provide evidence that inhibitors of 
      NF-kappaB signaling synergize with BET inhibition in in vitro and in vivo models,
      suggesting a clinical utility of these targeted therapies in patients with uveal 
      melanoma.
CI  - (c)2019 American Association for Cancer Research.
FAU - Ambrosini, Grazia
AU  - Ambrosini G
AD  - The Herbert Irving Comprehensive Cancer Center, Columbia University Medical
      Center, New York, New York. ga2391@cumc.columbia.edu.
FAU - Do, Catherine
AU  - Do C
AD  - Division of Genetics & Epigenetics, Department of Biomedical Research,
      Hackensack-Meridian Health School of Medicine at Seton Hall University, Nutley,
      New Jersey.
FAU - Tycko, Benjamin
AU  - Tycko B
AD  - Division of Genetics & Epigenetics, Department of Biomedical Research,
      Hackensack-Meridian Health School of Medicine at Seton Hall University, Nutley,
      New Jersey.
FAU - Realubit, Ronald B
AU  - Realubit RB
AD  - The Herbert Irving Comprehensive Cancer Center, Columbia University Medical
      Center, New York, New York.
FAU - Karan, Charles
AU  - Karan C
AD  - The Herbert Irving Comprehensive Cancer Center, Columbia University Medical
      Center, New York, New York.
FAU - Musi, Elgilda
AU  - Musi E
AD  - The Herbert Irving Comprehensive Cancer Center, Columbia University Medical
      Center, New York, New York.
FAU - Carvajal, Richard D
AU  - Carvajal RD
AD  - The Herbert Irving Comprehensive Cancer Center, Columbia University Medical
      Center, New York, New York.
AD  - Division of Hematology/Oncology, Columbia University Medical Center, New York,
      New York.
FAU - Chua, Vivian
AU  - Chua V
AUID- ORCID: https://orcid.org/0000-0002-1873-6820
AD  - Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University,
      Philadelphia, Pennsylvania.
FAU - Aplin, Andrew E
AU  - Aplin AE
AUID- ORCID: https://orcid.org/0000-0002-2734-3244
AD  - Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University,
      Philadelphia, Pennsylvania.
FAU - Schwartz, Gary K
AU  - Schwartz GK
AD  - The Herbert Irving Comprehensive Cancer Center, Columbia University Medical
      Center, New York, New York.
AD  - Division of Hematology/Oncology, Columbia University Medical Center, New York,
      New York.
LA  - eng
GR  - R01 CA160495/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20190318
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
EDAT- 2019/03/20 06:00
MHDA- 2019/03/20 06:00
CRDT- 2019/03/20 06:00
PHST- 2018/10/31 00:00 [received]
PHST- 2019/01/29 00:00 [revised]
PHST- 2019/03/13 00:00 [accepted]
PHST- 2019/03/20 06:00 [pubmed]
PHST- 2019/03/20 06:00 [medline]
PHST- 2019/03/20 06:00 [entrez]
AID - 0008-5472.CAN-18-3177 [pii]
AID - 10.1158/0008-5472.CAN-18-3177 [doi]
PST - ppublish
SO  - Cancer Res. 2019 May 1;79(9):2415-2425. doi: 10.1158/0008-5472.CAN-18-3177. Epub 
      2019 Mar 18.