NF1 Loss Promotes EGFR Activation and Confers Sensitivity to EGFR Inhibition in NF1-Mutant Melanoma.

Targeted therapies and immunotherapy have improved treatment outcomes for many patients with melanoma. However, patients whose melanomas harbor driver mutations in the neurofibromin 1 (NF1) tumor suppressor gene often lack effective targeted treatment options when their tumors do not respond to immunotherapy. In this study, we utilized patient-derived short-term cultures and multiomics approaches to identify molecular features that could inform the development of therapies for patients with NF1-mutant (NF1Mut) melanoma. Differential gene expression analysis revealed that EGFR is highly expressed and active in NF1Mut melanoma cells, in which it hyperactivates ERK and AKT, leading to increased tumor cell proliferation, survival, and growth. In contrast, genetic or pharmacologic inhibition of EGFR hindered cell proliferation and survival and suppressed tumor growth in patient-derived NF1Mut melanoma models but not in NF1 wild-type models. These results reveal a connection between NF1 loss and increased EGFR expression that is critical for the survival and growth of NF1Mut melanoma cells in patient-derived culture and xenograft models, irrespective of their BRAF and NRAS mutation status. SIGNIFICANCE: NF1 mutant melanomas rely on EGFR activation and can be effectively treated with the EGFR inhibitors cetuximab or afatinib, supporting further testing in clinical trials.