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

ABSTRACT: The nongenetic mechanisms required to control tumor phenotypic plasticity and shape drug-resistance remain unclear. We show here that the Aryl hydrocarbon Receptor (AhR) transcription factor directly regulates the gene expression program associated with the acquisition of resistance to BRAFi in melanoma. In addition, we show in melanoma cells that canonical activation of AhR mediates the activation of the SRC pathway and promotes the acquisition of an invasive and aggressive resistant phenotype to front-line BRAF inhibitor treatment in melanoma. This nongenetic reprogramming identifies a clinically-compatible approach to reverse BRAFi resistance in melanoma. Using a preclinical BRAFi resistant PDX melanoma model, we demonstrate that SRC inhibition with dasatinib significantly re-sensitizes

SUBMITTER: Anais Paris 

PROVIDER: S-SCDT-10_15252-EMMM_202215677 | biostudies-other |

REPOSITORIES: biostudies-other