The Pregnane X Receptor (PXR) contributes to phenotypic plasticity and modulates the sensitivity to targeted therapies in melanoma

Stable Pregnane X Receptor (PXR/NR1I2) expression in BRAF-mutated human melanoma cell lines sensitizes cells to combined BRAFi/MEKi treatment.

• Why it matters: Advanced metastatic melanoma often develops therapeutic resistance and recurrence, and tumor adaptation may be shaped by drug transport and metabolism programs controlled by PXR.
• What they did: The study measured significant, heterogeneous PXR expression in human melanoma samples, then tested MAPK inhibitor sensitivity in BRAF-mutated melanoma cell lines with stable PXR expression and used transcriptomics to link PXR to phenotypic markers, highlighting MITF in untreated PXR-overexpressing cells.
• The result: PXR-linked transcriptional programs suggest a shift toward a melanocytic phenotype associated with increased BRAFi/MEKi sensitivity, supporting PXR signature work to identify patients more likely to benefit and to develop PXR as a predictive biomarker.

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