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Loss of the Aryl Hydrocarbon Receptor (AhR) Promotes Cancer Cells Resistance to BRAFV600E Targeted Therapies. [CRISPR]

ABSTRACT: Predicting a patient’s response to chemotherapies and identifying additional molecular targets to improve treatment efficacy are major objectives in cancer research. BRAFV600E inhibitors targeting the MAP kinase pathway showed promising initial clinical results in thyroid cancers (TCs) for metastatic or recurrent tumors refractory to radioiodine treatments. BRAFV600E-targeted therapies have also been approved by the FDA for the treatment of some unresectable or metastatic BRAFV600E+ solid tumors. Still, for most patients, the response to BRAFV600E blocking therapy is transient due to cell proliferation reactivation through escape pathways. We performed a genome-wide CRISPR screen to reveal targets in TCs that facilitate resistance or sensitize thyroid cancer cells to inhibitors of the MAP kinase pathway. Among the genes that consistently altered MAPK inhibitor treatment response, we identified the Aryl hydrocarbon Receptor (AhR) and its molecular partner, the AhR nuclear translocator (ARNT). The AHR-ARNT heteroduplex is an environmental sensor that integrates extracellular, endogenous, and metabolic signals to equilibrate cell activity. Inactivation of AhR or ARNT increased TC cells' resistance to targeted therapies. Our study revealed that AhR-deficient cancer cells expressed elevated activity in genes linked to the TGFβ-mediated SMAD2/3 pathway after drug treatment. Our results suggest that SMAD2/3 competes to bind ARNT and that the loss of AhR gives cancer cells a potent escape pathway to targeted therapies, counteracting MAPK inhibition with SMAD activation to sustain cancer cell proliferation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286107 | GEO | 2025/01/12

REPOSITORIES: GEO

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Project description:BRAF oncogene is mutated in ~50% of human cutaneous melanomas. The BRAF V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway fuelling cancer growth. The inhibitors of BRAF V600E (BRAFi), lead to massive and high response rate. However, BRAFi-resistant cells that operate as a cellular reservoir for relapses severely limits the duration of the clinical response. The recent depiction of these resistant cells did not identify druggable targets to ensure long-term survival under BRAFi. Here, we identify the aryl hydrocarbon receptor (AhR) as a target to eradicate resistant cells. We show that BRAFi bind to AhR on a new site, named beta-pocket, and reprogram gene expression independently of its partner ARNT. beta-pocket activation induces a pigmentation signature, which is associated to BRAFi-induced cell death of sensitive BRAF V600E melanoma cells and tumour shrinkage. Intriguingly, in resistant cells, BRAFi does not induced a pigmentation signature since these cells display another AhR program; AhR-ARNT dependant. By this way, AhR directs several key BRAFi-resistant genes. At single cell level, this constitutive activation of AhR-ARNT is identified in rare cells before BRAFi-treatment of melanoma tumours and an enrichment of these alpha-cells is observed under BRAFi. Our data strongly suggest that an endogenous AhR ligand activates AhR-ARNT via the canonical AhR pocket (alpha-pocket), thus favouring BRAFi-resistant gene expression. Importantly, we identify the clinically compatible AhR antagonist, the resveratrol (RSV), able to abrogate the deleterious constitutive activation of AhR and to reduce the cellular reservoir for the relapse. Taken together, this work reveals that constitutive AhR signalling drives BRAFi resistance and constitutes a therapeutic target to achieve long-term patient survival under BRAFi. More broadly, the constitutive activation of AhR by endogenous ligands is in line with the ability of UV radiations to generate potent AhR ligands and to favour melanoma onset.