Fibroblast-derived neuregulin 1 promotes compensatory ErbB3 receptor signaling in mutant BRAF melanoma

Area of Science:

• Oncology
• Molecular Biology
• Dermatology

Background:

• Rapidly accelerated fibrosarcoma (RAF) inhibitors are frontline treatments for BRAF-mutant melanoma, but treatment response is variable.
• Adaptive signaling, including ErbB3 activation, contributes to resistance against targeted therapies.
• The source of neuregulin 1 (NRG1), the ErbB3 ligand, in BRAF-mutant melanoma was previously unknown.

Purpose of the Study:

• To identify the source of NRG1 in BRAF-mutant melanoma.
• To investigate the role of fibroblast-derived NRG1 in mediating resistance to RAF inhibitors.
• To evaluate the therapeutic potential of targeting the ErbB3/ErbB2 pathway in combination with RAF inhibitors.

Main Methods:

• Analysis of NRG1 expression in melanoma samples.
• Co-culture experiments with melanoma cells and fibroblasts/cancer-associated fibroblasts (CAFs).
• Assessment of ErbB3 pathway activation and cell viability under RAF inhibitor treatment.
• Inhibition of the ErbB3/ErbB2 pathway to assess its impact on drug resistance.

Main Results:

• Dermal fibroblasts and CAFs isolated from BRAF-mutant melanomas highly express NRG1.
• Conditioned medium from fibroblasts and CAFs activates the ErbB3 pathway and reduces RAF inhibitor efficacy in melanoma cells.
• Targeting the ErbB3/ErbB2 pathway partially overcomes NRG1-mediated resistance to RAF inhibitors.

Conclusions:

• NRG1 from tumor microenvironment fibroblasts promotes resistance to RAF inhibitors in BRAF-mutant melanoma via paracrine signaling.
• Combined inhibition of RAF and ErbB3/ErbB2 pathways may enhance therapeutic outcomes for melanoma patients.