Melanomas with concurrent BRAF non-p.V600 and NF1 loss-of-function mutations are targetable by BRAF/MEK inhibitor...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Targeted therapies for BRAF non-p.V600 mutant melanomas are limited.
• BRAF/MEK inhibitor combinations show survival benefits in BRAF p.V600 mutant melanomas.

Purpose of the Study:

• To investigate the molecular landscape of BRAF non-p.V600 mutant melanomas.
• To identify potential therapeutic strategies for this melanoma subtype.

Main Methods:

• Analysis of 772 cutaneous melanoma exomes.
• Cell signaling assays to study BRAF mutant signaling.
• In vitro and in vivo experiments with BRAF/MEK inhibitors.

Main Results:

• BRAF non-p.V600 mutations frequently co-occur with NF1 loss.
• BRAF non-p.V600 mutants signal as monomers and dimers in NF1 loss contexts.
• Combination BRAF/MEK inhibition reduced cell viability and tumor growth in preclinical models.

Conclusions:

• NF1 loss is a key factor in BRAF non-p.V600 mutant melanoma signaling.
• BRAF/MEK inhibitor combinations may benefit patients with BRAF non-p.V600 mutant melanomas and NF1 loss.
• Current FDA-approved BRAF/MEK inhibitor combinations could be repurposed for this patient group.