Role of Flavonoids in the Prevention of AhR-Dependent Resistance During Treatment with BRAF Inhibitors

Abstract

: BRAF and MEK inhibitors (BRAFi and MEKi) are the standard of care for the treatment of metastatic melanoma in patients with BRAFV600E 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 BRAFV600E) 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.

How the AHR Became Important in Cancer: The Role of Chronically Active AHR in Cancer Aggression

“…In addition to being hyper-expressed in some malignant cells, the AHR was shown, as early as 2000 [ 85 ], to be “constitutively active” in adult T cell leukemias [ 83 ] and cancers of the stomach [ 101 , 102 ], liver [ 103 , 104 ], prostate [ 105 ], head and neck [ 86 , 87 , 106 ], breast [ 100 , 107 , 108 , 109 ], brain [ 88 , 90 ], and skin [ 110 , 111 ]. The use of the term “constitutive” in this context reflected the field’s former lack of understanding about endogenous ligands in the tumor, and not the absence of chronic production of endogenous ligands (see Section 5.1 ).…”

AhR and Cancer: from Gene Profiling to Targeted Therapy

“…Flavonoids induce apoptosis and cellcycle arrest, the inhibition of metabolizing enzymes (notably cytochromes P450), the formation of reactive oxygen species (ROS), and the promotion of angiogenesis [89]. Several phase II clinical trials using flavonoids for cancer treatment have already been conducted for colorectal [90], breast [91], and prostate [92] cancer and melanoma [93]. However, their clinical use is limited due to inherent constrains, including their isolation/purification and pharmacokinetic challenges (e.g., bioavailability, drug-drug interactions, and metabolic instability) [89] [94].…”

Microbial Transformation of Galangin Derivatives and Cytotoxicity Evaluation of Their Metabolites

“…Flavonoids have been reported to demonstrate promising results when used against different tumor cell lines, including melanoma cells [4]. Furthermore, flavonoids naturally exhibit low toxicity in biological systems, which makes them an alternative therapy for the treatment of cancers in comparison with traditional anticancer drugs [5].…”