Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Combined anti-BRAF and anti-MEK therapy is standard for BRAF V600E metastatic melanoma.
• Tumor cell resistance, often via epithelial-to-mesenchymal transition (EMT), limits targeted therapy efficacy.
• EMT in melanoma involves decreased MITF, increased AXL, and RhoA-activated cytoskeleton changes, leading to invasiveness.

Purpose of the Study:

• To investigate the role of discoidin domain receptor 2 (DDR2) in melanoma therapy resistance.
• To evaluate DDR2 inhibition as a strategy against EMT-driven resistance and proliferation.

Main Methods:

• Analysis of DDR2 expression in human melanoma samples post-treatment and in resistant cell lines.
• Assessment of DDR2 inhibition effects on AXL expression, actin cytoskeleton, and cell proliferation in vitro and in vivo.
• Investigation of DDR2's impact on the MAP kinase pathway in resistant melanoma cells.

Main Results:

• Melanoma cells, particularly resistant ones exhibiting EMT, overexpress DDR2.
• DDR2 inhibition decreased AXL expression and actin stress fiber formation in resistant cells.
• DDR2 was found to control cell and tumor proliferation via the MAP kinase pathway in resistant melanoma.

Conclusions:

• DDR2 is upregulated in resistant melanoma cells undergoing EMT.
• Inhibiting DDR2 shows promise in overcoming EMT-driven resistance by reducing invasiveness and proliferation.
• Targeting DDR2 represents a potential new therapeutic strategy for overcoming resistance to BRAF/MEK inhibitors in melanoma.