Abstract
BRAF inhibitors target the BRAF-V600E/K mutated kinase, the driver mutation found in 50% of cutaneous melanoma. They give unprecedented anti-tumor responses but acquisition of resistance ultimately limits their clinical benefit. The master regulators driving the expression of resistance-genes remain poorly understood. Here, we demonstrate that the Aryl hydrocarbon Receptor (AhR) transcription factor is constitutively activated in a subset of melanoma cells, promoting the dedifferentiation of melanoma cells and the expression of BRAFi-resistance genes. Typically, under BRAFi pressure, death of BRAFi-sensitive cells leads to an enrichment of a small subpopulation of AhR-activated and BRAFi-persister cells, responsible for relapse. Also, differentiated and BRAFi-sensitive cells can be redirected towards an AhR-dependent resistant program using AhR agonists. We thus identify Resveratrol, a clinically compatible AhR-antagonist that abrogates deleterious AhR sustained-activation. Combined with BRAFi, Resveratrol reduces the number of BRAFi-resistant cells and delays tumor growth. We thus propose AhR-impairment as a strategy to overcome melanoma resistance.
Highlights
BRAF inhibitors target the BRAF-V600E/K mutated kinase, the driver mutation found in 50% of cutaneous melanoma
Vem failed to induce endogenous CYP1A1 expression (Fig. 1e) and CYP1A enzymatic activity (EROD) as observed with TCDD (Fig. 1f). These results indicated that Vem binds to Aryl hydrocarbon Receptor (AhR) differently than canonical AhR ligands
Docking experiments have demonstrated that Vem and the canonical AhR ligand/agonist TCDD interact with AhR at different positions (Fig. 1g)
Summary
BRAF inhibitors target the BRAF-V600E/K mutated kinase, the driver mutation found in 50% of cutaneous melanoma. It has recently been shown that acquisition of these BRAFi resistance programs arise in a subset of melanoma cells and is associated with a dedifferentiated status of the melanoma cells[10,11] Together, this increases the complexity and fosters the identification of the master regulators driving the expression of these resistance-genes that remain still unknown[12,13,14,15,16,17]. BRAFi constitute new AhR ligands promoting melanoma sensitivity while a small subpopulation of cells has a high canonical AhR activity that is responsible for resistance acquiring and relapse. This signature, which significantly overlaps with the classical melanoma proliferative signature[14,15], was only observed with β-pocket ligands (Vem, Dab) and not with αpocket ligands such as TCDD and Benzo(a)pyrene
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
