The AhR-SRC axis as a therapeutic vulnerability in BRAFi-resistant melanoma

The use of BRAF inhibitors, specific of the BRAFV600E mutation, as a therapeutic strategy for melanoma has significantly improved patient survival. However, resistance mechanisms appear systematically and limit the benefit of treatment. Here we show that AhR transcription factor participates in BRAFi resistance and is associated with the acquisition of an invasive and a dedifferentiated melanoma phenotype by controlling the expression of specific genes. AhR also induces the activation of the c-Src pathway through its phosphorylation, associated with BRAFi resistance. The use of a specific inhibitor of c-Src such as Dasatinib makes it possible to sensitize resistant cells to BRAFi and to prevent the acquisition of an invasive melanoma phenotype by regulating the expression of the AhR-dependent genes. mRNA expression profiles (RNAseq) in BRAFi sensitive and resistant melanoma cell lines invalidated or not for AhR transcription factor (CRISPR-Cas9), or after treatment by ITE, Dasatinib or Bosutinib (Src inhibitors)