Abstract 4703: EGFR is a promising therapeutic target in NF1 mutant melanoma

Abstract Background: Molecularly targeted therapies and immunotherapy improved treatment outcomes for melanoma patients. However, patients with driver mutations in the Neurofibromin 1 (NF1) tumor suppressor gene, which represent 20-30% of melanomas, have not benefitted from these treatment advances, underscoring an unmet clinical need. Methods: We compared 13 NF1 mutant (NF1Mut) and 19 NF1 wild-type (NF1WT) patient-derived short-term cultures (STCs) integrating multi-omic analysis of DNA mutations (Whole Exome Sequencing), RNA expression, and gene regulation (RNA-Seq, ATAC-Seq, H3K4Me3 and H3K27Ac). Independent melanoma patients’ specimens (n= 40) were used for immunohistochemical validation studies. We then used STCs for functional studies defining the role of NF1 loss in melanoma and testing potential therapeutic targets in-vitro and in PDX models. Results: Comparing NF1Mut to NF1WT uncovered gene regulatory elements (ATAC P = 0.024, H3K27Ac P = 0.011) controlling a significantly increased transcription of EGFR in NF1Mut (P = 0.005). The significant upregulation of EGFR expression was confirmed by western blotting (P = 0.003) and IHC in an independent melanoma patient cohort (P = 0.0007). Functional studies revealed that EGF rapidly activates EGFR, AKT and ERK in NF1Mut but not NF1WT melanoma cells (P < 0.0001). Moreover, NF1 knockdown in NF1WT in-vitro resulted in an increased melanoma cell proliferation (P < 0.0001) as well as, EGFR, AKT and ERK activation. Genetic or immunological EGFR inhibition blunted cell proliferation, cell survival, and tumor growth in NF1Mut but not NF1WT melanoma STCs (P < 0.0001) and PDX models (P < 0.0001) independent of BRAF or NRAS mutation status. Conclusion: Our study uncovers a stereotypical and transcriptionally controlled activation of the EGFR-AKT signaling axis in NF1Mut melanoma, with EGFR inhibition limiting tumor growth in NF1Mut but not NF1WT melanomas. Data suggest a possible role of targeting EGFR as therapeutic target in melanoma patients with NF1Mut tumors. Citation Format: Milad Ibrahim, Irineu Illa-Bochaca, George Jour, Eleazar Vega-Saenz de Miera, Kelly Ruggles, Jeffrey Weber, Markus Schober1, Iman Osman. EGFR is a promising therapeutic target in NF1 mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4703.