V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to ±. We investigated mechanisms for this and explored whether genotype affects response to immunotherapy.

Pretreatment formalin-fixed paraffin-embedded tumors from patients treated with ± underwent gene expression profiling and DNA sequencing. Molecular results were validated using The Cancer Genome Atlas (TCGA) data. An independent cohort of V600E/K patients treated with anti-PD-1 immunotherapy was examined.

Baseline tissue and clinical outcome with ± were studied in 93 patients (78 V600E, 15 V600K). V600K patients had numerically less tumor regression (median, -31% vs. -52%, = 0.154) and shorter progression-free survival (PFS; median, 5.7 vs. 7.1 months, = 0.15) compared with V600E. V600K melanomas had lower expression of the ERK pathway feedback regulator dual-specificity phosphatase 6, confirmed with TCGA data (116 V600E, 17 V600K). Pathway analysis showed V600K had lower expression of ERK and higher expression of PI3K-AKT genes than V600E. Higher mutational load was observed in V600K, with a higher proportion of mutations in and tumor-suppressor genes. In patients treated with anti-PD-1, V600K ( = 19) had superior outcomes than V600E ( = 84), including response rate (53% vs. 29%, = 0.059), PFS (median, 19 vs. 2.7 months, = 0.049), and overall survival (20.4 vs. 11.7 months, = 0.081).

V600K melanomas appear to benefit less from ± than V600E, potentially due to less reliance on ERK pathway activation and greater use of alternative pathways. In contrast, these melanomas have higher mutational load and respond better to immunotherapy.