PMID- 32708687
OWN - NLM
STAT- MEDLINE
DCOM- 20210222
LR  - 20210222
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 21
IP  - 14
DP  - 2020 Jul 16
TI  - Role of Flavonoids in the Prevention of AhR-Dependent Resistance During Treatment 
      with BRAF Inhibitors.
LID - 10.3390/ijms21145025 [doi]
LID - 5025
AB  - BRAF and MEK inhibitors (BRAFi and MEKi) are the standard of care for the 
      treatment of metastatic melanoma in patients with BRAF(V600E) mutations, greatly 
      improving progression-free survival. However, the acquisition of resistance to 
      BRAFi and MEKi remains a difficult clinical challenge, with limited therapeutic 
      options available for these patients. Here, we investigated the therapeutic 
      potential of natural flavonoids as specific AhR (Aryl hydrocarbon Receptor) 
      transcription factor antagonists in combination with BRAFi. EXPERIMENTAL DESIGN: 
      Experiments were performed in vitro and in vivo with various human melanoma cell 
      lines (mutated for BRAF(V600E)) sensitive or resistant to BRAFi. We evaluated the 
      role of various flavonoids on cell sensitivity to BRAFi and their ability to 
      counteract resistance and the invasive phenotype of melanoma. RESULTS: Flavonoids 
      were highly effective in potentiating BRAFi therapy in human melanoma cell lines 
      by increasing sensitivity and delaying the pool of resistant cells that arise 
      during treatment. As AhR antagonists, flavonoids counteracted a gene expression 
      program associated with the acquisition of resistance and phenotype switching 
      that leads to an invasive and EMT-like phenotype. CONCLUSIONS: The use of natural 
      flavonoids opens new therapeutic opportunities for the treatment of patients with 
      BRAF-resistant disease.
FAU - Leclair, Heloise M
AU  - Leclair HM
AD  - Institut de Genetique et Developpement de Rennes, University Rennes-UMR6290, 
      F-35000 Rennes, France.
FAU - Tardif, Nina
AU  - Tardif N
AUID- ORCID: 0000-0002-9855-2350
AD  - Institut de Genetique et Developpement de Rennes, University Rennes-UMR6290, 
      F-35000 Rennes, France.
FAU - Paris, Anais
AU  - Paris A
AD  - Institut de Genetique et Developpement de Rennes, University Rennes-UMR6290, 
      F-35000 Rennes, France.
FAU - Galibert, Marie-Dominique
AU  - Galibert MD
AUID- ORCID: 0000-0003-0095-742X
AD  - Institut de Genetique et Developpement de Rennes, University Rennes-UMR6290, 
      F-35000 Rennes, France.
AD  - Department of Molecular Genetics and Genomics, Hospital University of Rennes, 
      F-35000 Rennes, France.
FAU - Corre, Sebastien
AU  - Corre S
AUID- ORCID: 0000-0003-1532-5660
AD  - Institut de Genetique et Developpement de Rennes, University Rennes-UMR6290, 
      F-35000 Rennes, France.
LA  - eng
GR  - NA/ARC Foundation, France/
GR  - NA/Aviesan ITMO Cancer/
GR  - NA/INCA, France/
PT  - Journal Article
DEP - 20200716
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (AHR protein, human)
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Flavonoids)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
SB  - IM
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/*antagonists & inhibitors/metabolism
MH  - Cell Line, Tumor
MH  - Chick Embryo
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Flavonoids/*pharmacology
MH  - Humans
MH  - Melanoma/*drug therapy/metabolism
MH  - Models, Molecular
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins B-raf/*antagonists & inhibitors/metabolism
MH  - Receptors, Aryl Hydrocarbon/*antagonists & inhibitors/metabolism
PMC - PMC7404066
OTO - NOTNLM
OT  - AhR
OT  - BRAF inhibitor
OT  - flavonoids
OT  - melanoma
OT  - resistance
COIS- The authors declare no conflict of interest
EDAT- 2020/07/28 06:00
MHDA- 2021/02/23 06:00
PMCR- 2020/07/01
CRDT- 2020/07/26 06:00
PHST- 2020/06/02 00:00 [received]
PHST- 2020/07/03 00:00 [revised]
PHST- 2020/07/09 00:00 [accepted]
PHST- 2020/07/26 06:00 [entrez]
PHST- 2020/07/28 06:00 [pubmed]
PHST- 2021/02/23 06:00 [medline]
PHST- 2020/07/01 00:00 [pmc-release]
AID - ijms21145025 [pii]
AID - ijms-21-05025 [pii]
AID - 10.3390/ijms21145025 [doi]
PST - epublish
SO  - Int J Mol Sci. 2020 Jul 16;21(14):5025. doi: 10.3390/ijms21145025.