AXL inhibition improves BRAF-targeted treatment in melanoma

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Metastatic melanoma often develops resistance to standard therapies, limiting long-term survival.
• Tumor cell plasticity, including epithelial-mesenchymal transition associated with AXL expression, contributes to treatment resistance.
• AXL receptor tyrosine kinase is implicated in melanoma progression and therapeutic resistance.

Purpose of the Study:

• To investigate the therapeutic potential of the AXL inhibitor (AXLi) BGB324, alone and in combination with the BRAF inhibitor (BRAFi) vemurafenib.
• To evaluate the efficacy of combined AXLi and BRAFi therapy in preclinical models of metastatic melanoma.

Main Methods:

• AXL expression analysis in melanoma lymph node metastases.
• Ex vivo drug sensitivity assays.
• In vitro and in vivo studies using preclinical AXL-high melanoma models.
• Mechanistic investigations into drug interactions.

Main Results:

• AXL is expressed in the majority of melanoma lymph node metastases.
• Combination therapy of AXLi and BRAFi significantly reduced cell viability ex vivo.
• Therapeutic benefit observed in preclinical AXL-high melanoma models with combined AXLi and BRAFi treatment.
• AXLi potentiated BRAFi-induced apoptosis, stimulated ferroptosis, and inhibited autophagy.

Conclusions:

• AXL inhibition in combination with BRAF inhibition demonstrates significant therapeutic potential in metastatic melanoma.
• This combination strategy may overcome resistance mechanisms and improve treatment outcomes.
• AXLi represents a promising addition to standard therapy for metastatic melanoma.