Abstract Inactivating, oncogenic alterations in the tumor suppressor neurofibromin 1 (NF1), a RAS-GTPase, have been identified in approximately 4% of all cancers and in a significant subset of melanomas, nerve sheath tumors, and gliomas. While the MEK inhibitor selumetinib has been FDA approved for pediatric patients with Neurofibromatosis type 1 with benign plexiform neurofibromas arising from germline NF1 mutation, MEK inhibitors and other therapies targeting the MAPK pathway have had limited clinical benefit in patients with tumors driven by NF1-inactivation. In melanoma, inactivation of NF1 is insufficient to induce tumorigenesis. Sequencing data from 1,912 melanoma tumor/normal pairs generated as part of MSK-IMPACT identified oncogenic mutations in TP53 as the most significant event common to NF1-inactivated melanoma, with oncogenic BRAF mutations frequently co-occurrent. Given the lack of models for studying NF1 loss, a cohort of genetically engineered mice were generated with melanocyte-restricted conditional loss of Nf1fl/fl and/or Trp53fl/fl, and/or conditional gain of oncogenic BRAF V600E (BrafCA). Combined Nf1/Trp53 knockout induced hyperpigmentation and melanoma formation with features common to the human disease including pigmented melanocytic and amelanotic spindle-shaped neoplasms and S100-positive staining in most. Other genetic cohorts developed were BrafCA/Nf1 fl/fl/Trp53 fl/fl and BrafCA/Trp53 fl/fl (faster onset, high penetrance) and BrafCA/Nf1 fl/fl (latent onset, lower penetrance) mice. To facilitate preclinical and functional studies, 22 mouse tumor-derived, syngeneic, immunogenic cell lines were generated. As anticipated, loss of Nf1 conditioned the response to treatment with a BRAF monomer inhibitor (vemurafenib). While Nf1-inactivated cells were more sensitive to MEK inhibition (trametinib), or combined BRAF/MEK inhibition, as seen by suppression of ERK phosphorylation (pERK), cyclin D1 and DUSP6 expression, and cell proliferation, levels of pERK quickly rebounded. BRAF V600E/NF1/TP53-mutant cells were also transiently sensitive to combined inhibition of BRAF and the positive RAS adaptor SHP2 (using SHP099); with the rebound of pERK mitigated only by MEK, not upstream BRAF/SHP2, inhibition. In mice with established BrafCA/Nf1/Trp53-null tumors as well as in a genetically similar PDX of human melanoma (SK-MEL-1273A), combination strategies such as the triple regimen of RAF/MEK/SHP2 inhibitors induced more durable suppression of pERK and tumor regression. Studies evaluating vertical MAPK targeting strategies that include direct inhibition of RAS or inhibition of parallel survival pathways are ongoing in this molecularly defined cohort. Citation Format: Olvania-Danyca Hilaire, Alexis M. Jones, Moriah H. Nissan, Sebastien Monette, Jordan Eichholz, Cailian Liu, Xia Yang, Ayana Sawai-Frantz, Elisa de Stanchina, Taha Merghoub, Neal Rosen, David B. Solit, Aphrothiti J. Hanrahan. Vertical MAPK pathway targeting is required for tumor regression in novel human and mouse models of NF1-inactivated melanoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6059.
Hilaire et al. (Fri,) studied this question.